Insulated neighborhood: Difference between revisions
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[[File:InsulatedNeighborhood.svg|frame|right|Multiple levels of mammalian genome organization. Chromosomes occupy discrete territories in the nucleus (left). Topologically associating domains (TADs) are regions of the genome with locally high interaction frequency (center). Insulated neighborhoods are loops formed by the interaction of CTCF/cohesin-bound anchors containing genes and their regulatory elements.]] |
[[File:InsulatedNeighborhood.svg|frame|right|Multiple levels of mammalian genome organization. Chromosomes occupy discrete territories in the nucleus (left). Topologically associating domains (TADs) are regions of the genome with locally high interaction frequency (center). Insulated neighborhoods are loops formed by the interaction of CTCF/cohesin-bound anchors containing genes and their regulatory elements.]] |
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In [[mammal]]ian [[biology]], '''insulated neighborhoods''' (or "Chromatin loops") are [[chromosome|chromosomal]] loop structures formed by the physical interaction of two [[DNA]] loci bound by the [[transcription factor]] [[CTCF]] and co-occupied by [[cohesin]].<ref>{{cite journal |last1=Hnisz |first1=D |last2=Day |first2=DS |last3=Young |first3=RA |title=Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control. |journal=Cell |date=17 November 2016 |volume=167 |issue=5 |pages=1188–1200 |pmid=27863240 |pmc=5125522 |doi=10.1016/j.cell.2016.10.024}}</ref> Insulated neighborhoods are thought to be [[structural unit|structural]] and functional units of [[regulation of gene expression|gene control]] because their integrity is important for normal gene regulation. Current evidence suggests that these structures form the mechanistic underpinnings of higher-order chromosome structures, including [[topologically associating domain]]s (TADs). Insulated neighborhoods are functionally important in understanding gene regulation in normal cells and dysregulated gene expression in disease. |
In [[mammal]]ian [[biology]], '''insulated neighborhoods''' (or "Chromatin loops") are [[chromosome|chromosomal]] loop structures formed by the physical interaction of two [[DNA]] loci bound by the [[transcription factor]] [[CTCF]] and co-occupied by [[cohesin]].<ref>{{cite journal |last1=Hnisz |first1=D |last2=Day |first2=DS |last3=Young |first3=RA |author-link3=Richard A. Young|title=Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control. |journal=Cell |date=17 November 2016 |volume=167 |issue=5 |pages=1188–1200 |pmid=27863240 |pmc=5125522 |doi=10.1016/j.cell.2016.10.024}}</ref> Insulated neighborhoods are thought to be [[structural unit|structural]] and functional units of [[regulation of gene expression|gene control]] because their integrity is important for normal gene regulation. Current evidence suggests that these structures form the mechanistic underpinnings of higher-order chromosome structures, including [[topologically associating domain]]s (TADs). Insulated neighborhoods are functionally important in understanding gene regulation in normal cells and dysregulated gene expression in disease. |
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==Enhancer-gene targeting== |
==Enhancer-gene targeting== |
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==Function== |
==Function== |
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Insulated neighborhoods are defined as chromosome loops that are formed by CTCF [[homodimer]]s, co-bound with cohesin, and containing at least one gene.<ref>{{cite journal |last1=Dowen |first1=JM |last2=Fan |first2=ZP |last3=Hnisz |first3=D |last4=Ren |first4=G |last5=Abraham |first5=BJ |last6=Zhang |first6=LN |last7=Weintraub |first7=AS |last8=Schuijers |first8=J |last9=Lee |first9=TI|last10=Zhao|first10=K |last11=Young |first11=RA |title=Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes. |journal=Cell |date=9 October 2014 |volume=159 |issue=2 |pages=374–387 |pmid=25303531 |doi=10.1016/j.cell.2014.09.030 |pmc=4197132}}</ref><ref>{{cite journal |last1=Ji |first1=X |last2=Dadon |first2=DB |last3=Powell |first3=BE |last4=Fan |first4=ZP |last5=Borges-Rivera |first5=D |last6=Shachar |first6=S |last7=Weintraub |first7=AS |last8=Hnisz |first8=D |last9=Pegoraro |first9=G|last10=Lee|first10=TI |last11=Misteli |first11=T |last12=Jaenisch |first12=R |last13=Young |first13=RA |title=3D Chromosome Regulatory Landscape of Human Pluripotent Cells. |journal=Cell Stem Cell |date=4 February 2016 |volume=18 |issue=2 |pages=262–275 |pmid=26686465 |pmc=4848748 |doi=10.1016/j.stem.2015.11.007}}</ref> The CTCF/cohesin-bound regions delimiting an insulated neighborhood are called "anchors." One study in human [[Embryonic stem cell]]s identified ~13,000 insulated neighborhoods that, on average, each contained three genes and was about 90kb in size.<ref>{{cite journal |last1=Ji |first1=X |last2=Dadon |first2=DB |last3=Powell |first3=BE |last4=Fan |first4=ZP |last5=Borges-Rivera |first5=D |last6=Shachar |first6=S |last7=Weintraub |first7=AS |last8=Hnisz |first8=D |last9=Pegoraro |first9=G|last10=Lee|first10=TI |last11=Misteli |first11=T |last12=Jaenisch |first12=R |last13=Young |first13=RA |title=3D Chromosome Regulatory Landscape of Human Pluripotent Cells. |journal=Cell Stem Cell |date=4 February 2016 |volume=18 |issue=2 |pages=262–75 |pmid=26686465 |pmc=4848748 |doi=10.1016/j.stem.2015.11.007}}</ref> Two lines of evidence argue that the boundaries of insulated neighborhoods are insulating: 1) the vast majority (~90-97%) of enhancer-gene interactions are contained within insulated neighborhoods and 2) genetic perturbation of CTCF/cohesin-bound insulated neighborhood anchors leads to local gene dysregulation due to novel interactions outside of the neighborhood. |
Insulated neighborhoods are defined as chromosome loops that are formed by CTCF [[homodimer]]s, co-bound with cohesin, and containing at least one gene.<ref>{{cite journal |last1=Dowen |first1=JM |last2=Fan |first2=ZP |last3=Hnisz |first3=D |last4=Ren |first4=G |last5=Abraham |first5=BJ |last6=Zhang |first6=LN |last7=Weintraub |first7=AS |last8=Schuijers |first8=J |last9=Lee |first9=TI|last10=Zhao|first10=K |last11=Young |first11=RA |author-link11=Richard A. Young|title=Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes. |journal=Cell |date=9 October 2014 |volume=159 |issue=2 |pages=374–387 |pmid=25303531 |doi=10.1016/j.cell.2014.09.030 |pmc=4197132}}</ref><ref>{{cite journal |last1=Ji |first1=X |last2=Dadon |first2=DB |last3=Powell |first3=BE |last4=Fan |first4=ZP |last5=Borges-Rivera |first5=D |last6=Shachar |first6=S |last7=Weintraub |first7=AS |last8=Hnisz |first8=D |last9=Pegoraro |first9=G|last10=Lee|first10=TI |last11=Misteli |first11=T |last12=Jaenisch |first12=R |last13=Young |first13=RA|author-link13=Richard A. Young |title=3D Chromosome Regulatory Landscape of Human Pluripotent Cells. |journal=Cell Stem Cell |date=4 February 2016 |volume=18 |issue=2 |pages=262–275 |pmid=26686465 |pmc=4848748 |doi=10.1016/j.stem.2015.11.007}}</ref> The CTCF/cohesin-bound regions delimiting an insulated neighborhood are called "anchors." One study in human [[Embryonic stem cell]]s identified ~13,000 insulated neighborhoods that, on average, each contained three genes and was about 90kb in size.<ref>{{cite journal |last1=Ji |first1=X |last2=Dadon |first2=DB |last3=Powell |first3=BE |last4=Fan |first4=ZP |last5=Borges-Rivera |first5=D |last6=Shachar |first6=S |last7=Weintraub |first7=AS |last8=Hnisz |first8=D |last9=Pegoraro |first9=G|last10=Lee|first10=TI |last11=Misteli |first11=T |last12=Jaenisch |first12=R |last13=Young |first13=RA|author-link13=Richard A. Young |title=3D Chromosome Regulatory Landscape of Human Pluripotent Cells. |journal=Cell Stem Cell |date=4 February 2016 |volume=18 |issue=2 |pages=262–75 |pmid=26686465 |pmc=4848748 |doi=10.1016/j.stem.2015.11.007}}</ref> Two lines of evidence argue that the boundaries of insulated neighborhoods are insulating: 1) the vast majority (~90-97%) of enhancer-gene interactions are contained within insulated neighborhoods and 2) genetic perturbation of CTCF/cohesin-bound insulated neighborhood anchors leads to local gene dysregulation due to novel interactions outside of the neighborhood. |
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The majority of insulated neighborhoods appear to be maintained during development because CTCF binding and CTCF-CTCF loop structures are very similar across human cell types.<ref>{{cite journal |last1=Ji |first1=X |last2=Dadon |first2=DB |last3=Powell |first3=BE |last4=Fan |first4=ZP |last5=Borges-Rivera |first5=D |last6=Shachar |first6=S |last7=Weintraub |first7=AS |last8=Hnisz |first8=D |last9=Pegoraro |first9=G|last10=Lee|first10=TI |last11=Misteli |first11=T |last12=Jaenisch |first12=R |last13=Young |first13=RA |title=3D Chromosome Regulatory Landscape of Human Pluripotent Cells. |journal=Cell Stem Cell |date=4 February 2016 |volume=18 |issue=2 |pages=262–75 |pmid=26686465 |pmc=4848748 |doi=10.1016/j.stem.2015.11.007}}</ref><ref>{{cite journal |last1=Cuddapah |first1=S |last2=Jothi |first2=R |last3=Schones |first3=DE |last4=Roh |first4=TY |last5=Cui |first5=K |last6=Zhao |first6=K |title=Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains. |journal=Genome Research |date=January 2009 |volume=19 |issue=1 |pages=24–32 |pmid=19056695 |doi=10.1101/gr.082800.108 |pmc=2612964}}</ref> While the location of many insulated neighborhood structures are maintained across different cell types, the enhancer-gene interactions occurring within them are cell-type specific, consistent with the cell type-specific activity of enhancers.<ref>{{cite journal |last1=Ji |first1=X |last2=Dadon |first2=DB |last3=Powell |first3=BE |last4=Fan |first4=ZP |last5=Borges-Rivera |first5=D |last6=Shachar |first6=S |last7=Weintraub |first7=AS |last8=Hnisz |first8=D |last9=Pegoraro |first9=G|last10=Lee|first10=TI |last11=Misteli |first11=T |last12=Jaenisch |first12=R |last13=Young |first13=RA |title=3D Chromosome Regulatory Landscape of Human Pluripotent Cells. |journal=Cell Stem Cell |date=4 February 2016 |volume=18 |issue=2 |pages=262–75 |pmid=26686465 |pmc=4848748 |doi=10.1016/j.stem.2015.11.007}}</ref><ref>{{cite journal |last1=Smith |first1=EM |last2=Lajoie |first2=BR |last3=Jain |first3=G |last4=Dekker |first4=J|author-link4= |
The majority of insulated neighborhoods appear to be maintained during development because CTCF binding and CTCF-CTCF loop structures are very similar across human cell types.<ref>{{cite journal |last1=Ji |first1=X |last2=Dadon |first2=DB |last3=Powell |first3=BE |last4=Fan |first4=ZP |last5=Borges-Rivera |first5=D |last6=Shachar |first6=S |last7=Weintraub |first7=AS |last8=Hnisz |first8=D |last9=Pegoraro |first9=G|last10=Lee|first10=TI |last11=Misteli |first11=T |last12=Jaenisch |first12=R |last13=Young |first13=RA |author-link13=Richard A. Young|title=3D Chromosome Regulatory Landscape of Human Pluripotent Cells. |journal=Cell Stem Cell |date=4 February 2016 |volume=18 |issue=2 |pages=262–75 |pmid=26686465 |pmc=4848748 |doi=10.1016/j.stem.2015.11.007}}</ref><ref>{{cite journal |last1=Cuddapah |first1=S |last2=Jothi |first2=R |last3=Schones |first3=DE |last4=Roh |first4=TY |last5=Cui |first5=K |last6=Zhao |first6=K |title=Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains. |journal=Genome Research |date=January 2009 |volume=19 |issue=1 |pages=24–32 |pmid=19056695 |doi=10.1101/gr.082800.108 |pmc=2612964}}</ref> While the location of many insulated neighborhood structures are maintained across different cell types, the enhancer-gene interactions occurring within them are cell-type specific, consistent with the cell type-specific activity of enhancers.<ref>{{cite journal |last1=Ji |first1=X |last2=Dadon |first2=DB |last3=Powell |first3=BE |last4=Fan |first4=ZP |last5=Borges-Rivera |first5=D |last6=Shachar |first6=S |last7=Weintraub |first7=AS |last8=Hnisz |first8=D |last9=Pegoraro |first9=G|last10=Lee|first10=TI |last11=Misteli |first11=T |last12=Jaenisch |first12=R |last13=Young |first13=RA|author-link13=Richard A. Young |title=3D Chromosome Regulatory Landscape of Human Pluripotent Cells. |journal=Cell Stem Cell |date=4 February 2016 |volume=18 |issue=2 |pages=262–75 |pmid=26686465 |pmc=4848748 |doi=10.1016/j.stem.2015.11.007}}</ref><ref>{{cite journal |last1=Smith |first1=EM |last2=Lajoie |first2=BR |last3=Jain |first3=G |last4=Dekker |first4=J|author-link4= |
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Job Dekker |title=Invariant TAD Boundaries Constrain Cell-Type-Specific Looping Interactions between Promoters and Distal Elements around the CFTR Locus. |journal=American Journal of Human Genetics |date=7 January 2016 |volume=98 |issue=1 |pages=185–201 |pmid=26748519 |doi=10.1016/j.ajhg.2015.12.002 |pmc=4716690}}</ref> |
Job Dekker |title=Invariant TAD Boundaries Constrain Cell-Type-Specific Looping Interactions between Promoters and Distal Elements around the CFTR Locus. |journal=American Journal of Human Genetics |date=7 January 2016 |volume=98 |issue=1 |pages=185–201 |pmid=26748519 |doi=10.1016/j.ajhg.2015.12.002 |pmc=4716690}}</ref> |
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Topologically associating domains (TADs) are megabase-size regions of relatively high DNA interaction frequencies.<ref>{{cite journal |last1=Dixon |first1=JR |last2=Selvaraj |first2=S |last3=Yue |first3=F |last4=Kim |first4=A |last5=Li |first5=Y |last6=Shen |first6=Y |last7=Hu |first7=M |last8=Liu |first8=JS |last9=Ren |first9=B |title=Topological domains in mammalian genomes identified by analysis of chromatin interactions. |journal=Nature |date=11 April 2012 |volume=485 |issue=7398 |pages=376–80 |pmid=22495300 |doi=10.1038/nature11082 |pmc=3356448 |bibcode=2012Natur.485..376D}}</ref><ref>{{cite journal |last1=Nora |first1=EP |last2=Lajoie |first2=BR |last3=Schulz |first3=EG |last4=Giorgetti |first4=L |last5=Okamoto |first5=I |last6=Servant |first6=N |last7=Piolot |first7=T |last8=van Berkum |first8=NL |last9=Meisig |first9=J|last10=Sedat|first10=J |last11=Gribnau |first11=J |last12=Barillot |first12=E |last13=Blüthgen |first13=N |last14=Dekker |first14=J |author-link14= |
Topologically associating domains (TADs) are megabase-size regions of relatively high DNA interaction frequencies.<ref>{{cite journal |last1=Dixon |first1=JR |last2=Selvaraj |first2=S |last3=Yue |first3=F |last4=Kim |first4=A |last5=Li |first5=Y |last6=Shen |first6=Y |last7=Hu |first7=M |last8=Liu |first8=JS |last9=Ren |first9=B |title=Topological domains in mammalian genomes identified by analysis of chromatin interactions. |journal=Nature |date=11 April 2012 |volume=485 |issue=7398 |pages=376–80 |pmid=22495300 |doi=10.1038/nature11082 |pmc=3356448 |bibcode=2012Natur.485..376D}}</ref><ref>{{cite journal |last1=Nora |first1=EP |last2=Lajoie |first2=BR |last3=Schulz |first3=EG |last4=Giorgetti |first4=L |last5=Okamoto |first5=I |last6=Servant |first6=N |last7=Piolot |first7=T |last8=van Berkum |first8=NL |last9=Meisig |first9=J|last10=Sedat|first10=J |last11=Gribnau |first11=J |last12=Barillot |first12=E |last13=Blüthgen |first13=N |last14=Dekker |first14=J |author-link14= |
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Job Dekker |last15=Heard |first15=E |title=Spatial partitioning of the regulatory landscape of the X-inactivation centre. |journal=Nature |date=11 April 2012 |volume=485 |issue=7398 |pages=381–5 |pmid=22495304 |doi=10.1038/nature11049 |pmc=3555144 |bibcode=2012Natur.485..381N}}</ref> Mechanistic studies indicate TADs are single insulated neighborhoods or collections of insulated neighborhoods.<ref>{{cite journal |last1=Ji |first1=X |last2=Dadon |first2=DB |last3=Powell |first3=BE |last4=Fan |first4=ZP |last5=Borges-Rivera |first5=D |last6=Shachar |first6=S |last7=Weintraub |first7=AS |last8=Hnisz |first8=D |last9=Pegoraro |first9=G|last10=Lee|first10=TI |last11=Misteli |first11=T |last12=Jaenisch |first12=R |last13=Young |first13=RA |title=3D Chromosome Regulatory Landscape of Human Pluripotent Cells. |journal=Cell Stem Cell |date=4 February 2016 |volume=18 |issue=2 |pages=262–75 |pmid=26686465 |pmc=4848748 |doi=10.1016/j.stem.2015.11.007}}</ref> |
Job Dekker |last15=Heard |first15=E |title=Spatial partitioning of the regulatory landscape of the X-inactivation centre. |journal=Nature |date=11 April 2012 |volume=485 |issue=7398 |pages=381–5 |pmid=22495304 |doi=10.1038/nature11049 |pmc=3555144 |bibcode=2012Natur.485..381N}}</ref> Mechanistic studies indicate TADs are single insulated neighborhoods or collections of insulated neighborhoods.<ref>{{cite journal |last1=Ji |first1=X |last2=Dadon |first2=DB |last3=Powell |first3=BE |last4=Fan |first4=ZP |last5=Borges-Rivera |first5=D |last6=Shachar |first6=S |last7=Weintraub |first7=AS |last8=Hnisz |first8=D |last9=Pegoraro |first9=G|last10=Lee|first10=TI |last11=Misteli |first11=T |last12=Jaenisch |first12=R |last13=Young |first13=RA|author-link13=Richard A. Young |title=3D Chromosome Regulatory Landscape of Human Pluripotent Cells. |journal=Cell Stem Cell |date=4 February 2016 |volume=18 |issue=2 |pages=262–75 |pmid=26686465 |pmc=4848748 |doi=10.1016/j.stem.2015.11.007}}</ref> |
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==Relevance to human disease== |
==Relevance to human disease== |
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[[Genetic variation|Genetic]] and [[Epigenetics|epigenetic]] variation of insulated neighborhood anchors have been linked to several human diseases. One study of a genetic variant linked to [[asthma]] disrupts CTCF binding and insulated neighborhood formation.<ref>{{cite journal |last1=Tang |first1=Z |last2=Luo |first2=OJ |last3=Li |first3=X |last4=Zheng |first4=M |last5=Zhu |first5=JJ |last6=Szalaj |first6=P |last7=Trzaskoma |first7=P |last8=Magalska |first8=A |last9=Wlodarczyk |first9=J|last10=Ruszczycki|first10=B |last11=Michalski |first11=P |last12=Piecuch |first12=E |last13=Wang |first13=P |last14=Wang |first14=D |last15=Tian |first15=SZ |last16=Penrad-Mobayed |first16=M |last17=Sachs |first17=LM |last18=Ruan |first18=X |last19=Wei |first19=CL|last20=Liu|first20=ET |last21=Wilczynski |first21=GM |last22=Plewczynski |first22=D |last23=Li |first23=G |last24=Ruan |first24=Y |title=CTCF-Mediated Human 3D Genome Architecture Reveals Chromatin Topology for Transcription. |journal=Cell |date=17 December 2015 |volume=163 |issue=7 |pages=1611–27 |pmid=26686651 |doi=10.1016/j.cell.2015.11.024 |pmc=4734140}}</ref> Studies of [[Genomic imprinting|imprinted]] loci showed [[DNA methylation]] controls CTCF-anchored loops regulating gene expression. Individuals with methylation aberrations at an imprinted CTCF-binding site near ''IGF2/H19'' form aberrant Insulated Neighborhoods and develop [[Beckwith–Wiedemann syndrome|Beckwith-Wiedemann syndrome]] (when both alleles have the paternal type of insulated neighborhood) or [[Silver–Russell syndrome|Silver-Russell syndrome]] (when both alleles have the maternal type of insulated neighborhood).<ref>{{cite journal |last1=Nativio |first1=R |last2=Sparago |first2=A |last3=Ito |first3=Y |last4=Weksberg |first4=R |last5=Riccio |first5=A |last6=Murrell |first6=A |title=Disruption of genomic neighbourhood at the imprinted IGF2-H19 locus in Beckwith-Wiedemann syndrome and Silver-Russell syndrome. |journal=Human Molecular Genetics |date=1 April 2011 |volume=20 |issue=7 |pages=1363–74 |pmid=21282187 |doi=10.1093/hmg/ddr018 |pmc=3049359}}</ref> |
[[Genetic variation|Genetic]] and [[Epigenetics|epigenetic]] variation of insulated neighborhood anchors have been linked to several human diseases. One study of a genetic variant linked to [[asthma]] disrupts CTCF binding and insulated neighborhood formation.<ref>{{cite journal |last1=Tang |first1=Z |last2=Luo |first2=OJ |last3=Li |first3=X |last4=Zheng |first4=M |last5=Zhu |first5=JJ |last6=Szalaj |first6=P |last7=Trzaskoma |first7=P |last8=Magalska |first8=A |last9=Wlodarczyk |first9=J|last10=Ruszczycki|first10=B |last11=Michalski |first11=P |last12=Piecuch |first12=E |last13=Wang |first13=P |last14=Wang |first14=D |last15=Tian |first15=SZ |last16=Penrad-Mobayed |first16=M |last17=Sachs |first17=LM |last18=Ruan |first18=X |last19=Wei |first19=CL|last20=Liu|first20=ET |last21=Wilczynski |first21=GM |last22=Plewczynski |first22=D |last23=Li |first23=G |last24=Ruan |first24=Y |title=CTCF-Mediated Human 3D Genome Architecture Reveals Chromatin Topology for Transcription. |journal=Cell |date=17 December 2015 |volume=163 |issue=7 |pages=1611–27 |pmid=26686651 |doi=10.1016/j.cell.2015.11.024 |pmc=4734140}}</ref> Studies of [[Genomic imprinting|imprinted]] loci showed [[DNA methylation]] controls CTCF-anchored loops regulating gene expression. Individuals with methylation aberrations at an imprinted CTCF-binding site near ''IGF2/H19'' form aberrant Insulated Neighborhoods and develop [[Beckwith–Wiedemann syndrome|Beckwith-Wiedemann syndrome]] (when both alleles have the paternal type of insulated neighborhood) or [[Silver–Russell syndrome|Silver-Russell syndrome]] (when both alleles have the maternal type of insulated neighborhood).<ref>{{cite journal |last1=Nativio |first1=R |last2=Sparago |first2=A |last3=Ito |first3=Y |last4=Weksberg |first4=R |last5=Riccio |first5=A |last6=Murrell |first6=A |title=Disruption of genomic neighbourhood at the imprinted IGF2-H19 locus in Beckwith-Wiedemann syndrome and Silver-Russell syndrome. |journal=Human Molecular Genetics |date=1 April 2011 |volume=20 |issue=7 |pages=1363–74 |pmid=21282187 |doi=10.1093/hmg/ddr018 |pmc=3049359}}</ref> |
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Insulated neighborhoods aid in identifying the target genes of disease-associated enhancer variants. The majority of disease-linked DNA variants identified from [[Genome-wide association study|genome-wide association studies]] occur in enhancers.<ref>{{cite journal |last1=Ernst |first1=J |last2=Kheradpour |first2=P |last3=Mikkelsen |first3=TS |last4=Shoresh |first4=N |last5=Ward |first5=LD |last6=Epstein |first6=CB |last7=Zhang |first7=X |last8=Wang |first8=L |last9=Issner |first9=R|last10=Coyne|first10=M |last11=Ku |first11=M |last12=Durham |first12=T |last13=Kellis |first13=M |last14=Bernstein |first14=BE |title=Mapping and analysis of chromatin state dynamics in nine human cell types. |journal=Nature |date=5 May 2011 |volume=473 |issue=7345 |pages=43–9 |pmid=21441907 |doi=10.1038/nature09906 |pmc=3088773 |bibcode=2011Natur.473...43E}}</ref><ref>{{cite journal |last1=Farh |first1=KK |last2=Marson |first2=A |last3=Zhu |first3=J |last4=Kleinewietfeld |first4=M |last5=Housley |first5=WJ |last6=Beik |first6=S |last7=Shoresh |first7=N |last8=Whitton |first8=H |last9=Ryan |first9=RJ|last10=Shishkin|first10=AA |last11=Hatan |first11=M |last12=Carrasco-Alfonso |first12=MJ |last13=Mayer |first13=D |last14=Luckey |first14=CJ |last15=Patsopoulos |first15=NA |last16=De Jager |first16=PL |last17=Kuchroo |first17=VK |last18=Epstein |first18=CB |last19=Daly |first19=MJ|last20=Hafler|first20=DA |last21=Bernstein |first21=BE |title=Genetic and epigenetic fine mapping of causal autoimmune disease variants. |journal=Nature |date=19 February 2015 |volume=518 |issue=7539 |pages=337–43 |pmid=25363779 |doi=10.1038/nature13835 |pmc=4336207 |bibcode=2015Natur.518..337F}}</ref><ref>{{cite journal |last1=Hnisz |first1=D |last2=Abraham |first2=BJ |last3=Lee |first3=TI |last4=Lau |first4=A |last5=Saint-André |first5=V |last6=Sigova |first6=AA |last7=Hoke |first7=HA |last8=Young |first8=RA |title=Super-enhancers in the control of cell identity and disease. |journal=Cell |date=7 November 2013 |volume=155 |issue=4 |pages=934–47 |pmid=24119843 |doi=10.1016/j.cell.2013.09.053 |pmc=3841062}}</ref><ref>{{cite journal |last1=Maurano |first1=MT |last2=Humbert |first2=R |last3=Rynes |first3=E |last4=Thurman |first4=RE |last5=Haugen |first5=E |last6=Wang |first6=H |last7=Reynolds |first7=AP |last8=Sandstrom |first8=R |last9=Qu |first9=H|last10=Brody|first10=J |last11=Shafer |first11=A |last12=Neri |first12=F |last13=Lee |first13=K |last14=Kutyavin |first14=T |last15=Stehling-Sun |first15=S |last16=Johnson |first16=AK |last17=Canfield |first17=TK |last18=Giste |first18=E |last19=Diegel |first19=M|last20=Bates|first20=D |last21=Hansen |first21=RS |last22=Neph |first22=S |last23=Sabo |first23=PJ |last24=Heimfeld |first24=S |last25=Raubitschek |first25=A |last26=Ziegler |first26=S |last27=Cotsapas |first27=C |last28=Sotoodehnia |first28=N |last29=Glass |first29=I|last30=Sunyaev|first30=SR |last31=Kaul |first31=R |last32=Stamatoyannopoulos |first32=JA |title=Systematic localization of common disease-associated variation in regulatory DNA. |journal=Science |date=7 September 2012 |volume=337 |issue=6099 |pages=1190–5 |pmid=22955828 |doi=10.1126/science.1222794 |pmc=3771521 |bibcode=2012Sci...337.1190M}}</ref> Identifying target genes of enhancers with disease-linked variants has been difficult because enhancers may act over long distances, but the constraint on enhancer-gene targeting by insulated neighborhoods refines the prediction of target genes. For example, a DNA variant associated with [[Diabetes mellitus type 2|type 2 diabetes]] occurs within an enhancer located between the ''CDC123'' and ''CAMK1D'' genes but only affects ''CAMK1D'' because this gene and the enhancer are within the same insulated neighborhood, while ''CDC123'' lies outside the neighborhood.<ref>{{cite journal |last1=Fogarty |first1=MP |last2=Cannon |first2=ME |last3=Vadlamudi |first3=S |last4=Gaulton |first4=KJ |last5=Mohlke |first5=KL |title=Identification of a regulatory variant that binds FOXA1 and FOXA2 at the CDC123/CAMK1D type 2 diabetes GWAS locus. |journal=PLOS Genetics |date=11 September 2014 |volume=10 |issue=9 |pages=e1004633 |pmid=25211022 |doi=10.1371/journal.pgen.1004633 |pmc=4161327 |doi-access=free }}</ref><ref>{{cite journal |last1=GTEx |first1=Consortium. |title=Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. |journal=Science |date=8 May 2015 |volume=348 |issue=6235 |pages=648–60 |pmid=25954001 |doi=10.1126/science.1262110 |pmc=4547484 |bibcode=2015Sci...348..648.}}</ref> |
Insulated neighborhoods aid in identifying the target genes of disease-associated enhancer variants. The majority of disease-linked DNA variants identified from [[Genome-wide association study|genome-wide association studies]] occur in enhancers.<ref>{{cite journal |last1=Ernst |first1=J |last2=Kheradpour |first2=P |last3=Mikkelsen |first3=TS |last4=Shoresh |first4=N |last5=Ward |first5=LD |last6=Epstein |first6=CB |last7=Zhang |first7=X |last8=Wang |first8=L |last9=Issner |first9=R|last10=Coyne|first10=M |last11=Ku |first11=M |last12=Durham |first12=T |last13=Kellis |first13=M |last14=Bernstein |first14=BE |title=Mapping and analysis of chromatin state dynamics in nine human cell types. |journal=Nature |date=5 May 2011 |volume=473 |issue=7345 |pages=43–9 |pmid=21441907 |doi=10.1038/nature09906 |pmc=3088773 |bibcode=2011Natur.473...43E}}</ref><ref>{{cite journal |last1=Farh |first1=KK |last2=Marson |first2=A |last3=Zhu |first3=J |last4=Kleinewietfeld |first4=M |last5=Housley |first5=WJ |last6=Beik |first6=S |last7=Shoresh |first7=N |last8=Whitton |first8=H |last9=Ryan |first9=RJ|last10=Shishkin|first10=AA |last11=Hatan |first11=M |last12=Carrasco-Alfonso |first12=MJ |last13=Mayer |first13=D |last14=Luckey |first14=CJ |last15=Patsopoulos |first15=NA |last16=De Jager |first16=PL |last17=Kuchroo |first17=VK |last18=Epstein |first18=CB |last19=Daly |first19=MJ|last20=Hafler|first20=DA |last21=Bernstein |first21=BE |title=Genetic and epigenetic fine mapping of causal autoimmune disease variants. |journal=Nature |date=19 February 2015 |volume=518 |issue=7539 |pages=337–43 |pmid=25363779 |doi=10.1038/nature13835 |pmc=4336207 |bibcode=2015Natur.518..337F}}</ref><ref>{{cite journal |last1=Hnisz |first1=D |last2=Abraham |first2=BJ |last3=Lee |first3=TI |last4=Lau |first4=A |last5=Saint-André |first5=V |last6=Sigova |first6=AA |last7=Hoke |first7=HA |last8=Young |first8=RA |author-link8=Richard A. Young|title=Super-enhancers in the control of cell identity and disease. |journal=Cell |date=7 November 2013 |volume=155 |issue=4 |pages=934–47 |pmid=24119843 |doi=10.1016/j.cell.2013.09.053 |pmc=3841062}}</ref><ref>{{cite journal |last1=Maurano |first1=MT |last2=Humbert |first2=R |last3=Rynes |first3=E |last4=Thurman |first4=RE |last5=Haugen |first5=E |last6=Wang |first6=H |last7=Reynolds |first7=AP |last8=Sandstrom |first8=R |last9=Qu |first9=H|last10=Brody|first10=J |last11=Shafer |first11=A |last12=Neri |first12=F |last13=Lee |first13=K |last14=Kutyavin |first14=T |last15=Stehling-Sun |first15=S |last16=Johnson |first16=AK |last17=Canfield |first17=TK |last18=Giste |first18=E |last19=Diegel |first19=M|last20=Bates|first20=D |last21=Hansen |first21=RS |last22=Neph |first22=S |last23=Sabo |first23=PJ |last24=Heimfeld |first24=S |last25=Raubitschek |first25=A |last26=Ziegler |first26=S |last27=Cotsapas |first27=C |last28=Sotoodehnia |first28=N |last29=Glass |first29=I|last30=Sunyaev|first30=SR |last31=Kaul |first31=R |last32=Stamatoyannopoulos |first32=JA |title=Systematic localization of common disease-associated variation in regulatory DNA. |journal=Science |date=7 September 2012 |volume=337 |issue=6099 |pages=1190–5 |pmid=22955828 |doi=10.1126/science.1222794 |pmc=3771521 |bibcode=2012Sci...337.1190M}}</ref> Identifying target genes of enhancers with disease-linked variants has been difficult because enhancers may act over long distances, but the constraint on enhancer-gene targeting by insulated neighborhoods refines the prediction of target genes. For example, a DNA variant associated with [[Diabetes mellitus type 2|type 2 diabetes]] occurs within an enhancer located between the ''CDC123'' and ''CAMK1D'' genes but only affects ''CAMK1D'' because this gene and the enhancer are within the same insulated neighborhood, while ''CDC123'' lies outside the neighborhood.<ref>{{cite journal |last1=Fogarty |first1=MP |last2=Cannon |first2=ME |last3=Vadlamudi |first3=S |last4=Gaulton |first4=KJ |last5=Mohlke |first5=KL |title=Identification of a regulatory variant that binds FOXA1 and FOXA2 at the CDC123/CAMK1D type 2 diabetes GWAS locus. |journal=PLOS Genetics |date=11 September 2014 |volume=10 |issue=9 |pages=e1004633 |pmid=25211022 |doi=10.1371/journal.pgen.1004633 |pmc=4161327 |doi-access=free }}</ref><ref>{{cite journal |last1=GTEx |first1=Consortium. |title=Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. |journal=Science |date=8 May 2015 |volume=348 |issue=6235 |pages=648–60 |pmid=25954001 |doi=10.1126/science.1262110 |pmc=4547484 |bibcode=2015Sci...348..648.}}</ref> |
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[[Mutation#Somatic mutations|Somatic mutations]] that alter insulated neighborhood anchors can contribute to [[Carcinogenesis|tumorigenesis]]. Chromosomal alterations such as [[Chromosomal translocation|translocations]], [[Deletion (genetics)|deletions]] and tandem duplications intersecting with insulated neighborhood anchor sites can activate [[oncogene]]s.<ref>{{cite journal |last1=Gröschel |first1=S |last2=Sanders |first2=MA |last3=Hoogenboezem |first3=R |last4=de Wit |first4=E |last5=Bouwman |first5=BA |last6=Erpelinck |first6=C |last7=van der Velden |first7=VH |last8=Havermans |first8=M |last9=Avellino |first9=R|last10=van Lom|first10=K |last11=Rombouts |first11=EJ |last12=van Duin |first12=M |last13=Döhner |first13=K |last14=Beverloo |first14=HB |last15=Bradner |first15=JE |last16=Döhner |first16=H |last17=Löwenberg |first17=B |last18=Valk |first18=PJ |last19=Bindels |first19=EM|last20=de Laat|first20=W |last21=Delwel |first21=R |title=A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. |journal=Cell |date=10 April 2014 |volume=157 |issue=2 |pages=369–81 |pmid=24703711 |doi=10.1016/j.cell.2014.02.019|doi-access=free}}</ref><ref>{{cite journal |last1=Hnisz |first1=D |last2=Weintraub |first2=AS |last3=Day |first3=DS |last4=Valton |first4=AL |last5=Bak |first5=RO |last6=Li |first6=CH |last7=Goldmann |first7=J |last8=Lajoie |first8=BR |last9=Fan |first9=ZP|last10=Sigova|first10=AA |last11=Reddy |first11=J |last12=Borges-Rivera |first12=D |last13=Lee |first13=TI |last14=Jaenisch |first14=R |last15=Porteus |first15=MH |last16=Dekker |first16=J |author-link16= |
[[Mutation#Somatic mutations|Somatic mutations]] that alter insulated neighborhood anchors can contribute to [[Carcinogenesis|tumorigenesis]]. Chromosomal alterations such as [[Chromosomal translocation|translocations]], [[Deletion (genetics)|deletions]] and tandem duplications intersecting with insulated neighborhood anchor sites can activate [[oncogene]]s.<ref>{{cite journal |last1=Gröschel |first1=S |last2=Sanders |first2=MA |last3=Hoogenboezem |first3=R |last4=de Wit |first4=E |last5=Bouwman |first5=BA |last6=Erpelinck |first6=C |last7=van der Velden |first7=VH |last8=Havermans |first8=M |last9=Avellino |first9=R|last10=van Lom|first10=K |last11=Rombouts |first11=EJ |last12=van Duin |first12=M |last13=Döhner |first13=K |last14=Beverloo |first14=HB |last15=Bradner |first15=JE |last16=Döhner |first16=H |last17=Löwenberg |first17=B |last18=Valk |first18=PJ |last19=Bindels |first19=EM|last20=de Laat|first20=W |last21=Delwel |first21=R |title=A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. |journal=Cell |date=10 April 2014 |volume=157 |issue=2 |pages=369–81 |pmid=24703711 |doi=10.1016/j.cell.2014.02.019|doi-access=free}}</ref><ref>{{cite journal |last1=Hnisz |first1=D |last2=Weintraub |first2=AS |last3=Day |first3=DS |last4=Valton |first4=AL |last5=Bak |first5=RO |last6=Li |first6=CH |last7=Goldmann |first7=J |last8=Lajoie |first8=BR |last9=Fan |first9=ZP|last10=Sigova|first10=AA |last11=Reddy |first11=J |last12=Borges-Rivera |first12=D |last13=Lee |first13=TI |last14=Jaenisch |first14=R |last15=Porteus |first15=MH |last16=Dekker |first16=J |author-link16= Job Dekker |last17=Young |first17=RA |author-link17=Richard A. Young|title=Activation of proto-oncogenes by disruption of chromosome neighborhoods. |journal=Science |date=25 March 2016 |volume=351 |issue=6280 |pages=1454–8 |pmid=26940867 |doi=10.1126/science.aad9024 |pmc=4884612 |bibcode=2016Sci...351.1454H}}</ref><ref>{{Cite journal |pmid=27869826 |pmc=5791882 |year=2016 |last1=Weischenfeldt |first1=Joachim |title=Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking |url= |journal=Nature Genetics |last2=Dubash |first2=Taronish |last3=Drainas |first3=Alexandros P. |last4=Mardin |first4=Balca R. |last5=Chen |first5=Yuanyuan |last6=Stütz |first6=Adrian M. |last7=Waszak |first7=Sebsatian M. |last8=Bosco |first8=Graziella |last9=Halvorsen |first9=Ann R.| last10 = Raeder| first10 = Benjamin |last11=Efthymiopoulos |first11=Theocharis |last12=Erkek |first12=Serap |last13=Siegl |first13=Christine |last14=Brenner |first14=Hermann |last15=Brustugun |first15=Odd T. |last16=Dieter |first16=Sebastian M |last17=Northcott |first17=Paul A. |last18=Petersen |first18=Iver |last19=Pfister |first19=Stefan M.| last20 = Schneider | first20 = Martin |last21=Solberg |first21=Steinar K. |last22=Thunissen |first22=Erik |last23=Weichert |first23=Wilko |last24=Zichner |first24=Thomas |last25=Thomas |first25=Roman |last26=Peifer |first26=Martin |last27=Helland |first27=Aslaug |last28=Ball |first28=Claudia R. |last29=Jechlinger |first29=Martin| last30 = Sotillo| first30 = Rocio |last31=Glimm |first31=Hanno |last32=Korbel |first32=Jan O. |author-link32=Jan O. Korbel |doi=10.1038/ng.3722 |volume=49 |issue=1 |pages=65–74}}</ref> Epigenetic dysregulation can also contribute to tumorigenesis by altering insulated neighborhoods. ''IDH''-mutant [[glioma]]s display altered DNA methylation patterns, so CTCF binding, which is DNA methylation-dependent, is also altered.<ref>{{cite journal |last1=Flavahan |first1=WA |last2=Drier |first2=Y |last3=Liau |first3=BB |last4=Gillespie |first4=SM |last5=Venteicher |first5=AS |last6=Stemmer-Rachamimov |first6=AO |last7=Suvà |first7=ML |last8=Bernstein |first8=BE |title=Insulator dysfunction and oncogene activation in IDH mutant gliomas. |journal=Nature |date=7 January 2016 |volume=529 |issue=7584 |pages=110–4 |pmid=26700815 |doi=10.1038/nature16490 |pmc=4831574 |url=https://dash.harvard.edu/bitstream/handle/1/27662216/4831574.pdf?sequence=1 |bibcode=2016Natur.529..110F}}</ref> Altered CTCF-binding disrupts insulated neighborhoods and can lead to oncogene misregulation. |
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Job Dekker |last17=Young |first17=RA |title=Activation of proto-oncogenes by disruption of chromosome neighborhoods. |journal=Science |date=25 March 2016 |volume=351 |issue=6280 |pages=1454–8 |pmid=26940867 |doi=10.1126/science.aad9024 |pmc=4884612 |bibcode=2016Sci...351.1454H}}</ref><ref>{{Cite journal |pmid=27869826 |pmc=5791882 |year=2016 |last1=Weischenfeldt |first1=Joachim |title=Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking |url= |journal=Nature Genetics |last2=Dubash |first2=Taronish |last3=Drainas |first3=Alexandros P. |last4=Mardin |first4=Balca R. |last5=Chen |first5=Yuanyuan |last6=Stütz |first6=Adrian M. |last7=Waszak |first7=Sebsatian M. |last8=Bosco |first8=Graziella |last9=Halvorsen |first9=Ann R.| last10 = Raeder| first10 = Benjamin |last11=Efthymiopoulos |first11=Theocharis |last12=Erkek |first12=Serap |last13=Siegl |first13=Christine |last14=Brenner |first14=Hermann |last15=Brustugun |first15=Odd T. |last16=Dieter |first16=Sebastian M |last17=Northcott |first17=Paul A. |last18=Petersen |first18=Iver |last19=Pfister |first19=Stefan M.| last20 = Schneider | first20 = Martin |last21=Solberg |first21=Steinar K. |last22=Thunissen |first22=Erik |last23=Weichert |first23=Wilko |last24=Zichner |first24=Thomas |last25=Thomas |first25=Roman |last26=Peifer |first26=Martin |last27=Helland |first27=Aslaug |last28=Ball |first28=Claudia R. |last29=Jechlinger |first29=Martin| last30 = Sotillo| first30 = Rocio |last31=Glimm |first31=Hanno |last32=Korbel |first32=Jan O. |author-link32=Jan O. Korbel |doi=10.1038/ng.3722 |volume=49 |issue=1 |pages=65–74}}</ref> Epigenetic dysregulation can also contribute to tumorigenesis by altering insulated neighborhoods. ''IDH''-mutant [[glioma]]s display altered DNA methylation patterns, so CTCF binding, which is DNA methylation-dependent, is also altered.<ref>{{cite journal |last1=Flavahan |first1=WA |last2=Drier |first2=Y |last3=Liau |first3=BB |last4=Gillespie |first4=SM |last5=Venteicher |first5=AS |last6=Stemmer-Rachamimov |first6=AO |last7=Suvà |first7=ML |last8=Bernstein |first8=BE |title=Insulator dysfunction and oncogene activation in IDH mutant gliomas. |journal=Nature |date=7 January 2016 |volume=529 |issue=7584 |pages=110–4 |pmid=26700815 |doi=10.1038/nature16490 |pmc=4831574 |url=https://dash.harvard.edu/bitstream/handle/1/27662216/4831574.pdf?sequence=1 |bibcode=2016Natur.529..110F}}</ref> Altered CTCF-binding disrupts insulated neighborhoods and can lead to oncogene misregulation. |
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== References == |
== References == |
Revision as of 03:26, 5 May 2024
In mammalian biology, insulated neighborhoods (or "Chromatin loops") are chromosomal loop structures formed by the physical interaction of two DNA loci bound by the transcription factor CTCF and co-occupied by cohesin.[1] Insulated neighborhoods are thought to be structural and functional units of gene control because their integrity is important for normal gene regulation. Current evidence suggests that these structures form the mechanistic underpinnings of higher-order chromosome structures, including topologically associating domains (TADs). Insulated neighborhoods are functionally important in understanding gene regulation in normal cells and dysregulated gene expression in disease.
Enhancer-gene targeting
Mammalian gene transcription is generally controlled by enhancers.[2][3][4][5][6] Enhancers can regulate transcription of genes at large distances by looping to physically contact their target genes. This property of enhancers makes it difficult to identify an enhancer's target gene(s). Insulators, another type of DNA regulatory element, limit an enhancer's ability to target distal genes when the insulator is located between an enhancer and a potential target.[7][8][9][10] In mammals, insulators are bound by CTCF,[11] but only a minority of CTCF-bound sites function as insulators.[12] CTCF molecules can form homodimers on DNA, which can be co-bound by cohesin; this chromatin loop structure helps constrain the ability of enhancers within the loop to target genes outside the loop. Loops with CTCF and cohesin at the start and end of the loop that restrict enhancer-gene targeting are "insulated neighborhoods."
Function
Insulated neighborhoods are defined as chromosome loops that are formed by CTCF homodimers, co-bound with cohesin, and containing at least one gene.[13][14] The CTCF/cohesin-bound regions delimiting an insulated neighborhood are called "anchors." One study in human Embryonic stem cells identified ~13,000 insulated neighborhoods that, on average, each contained three genes and was about 90kb in size.[15] Two lines of evidence argue that the boundaries of insulated neighborhoods are insulating: 1) the vast majority (~90-97%) of enhancer-gene interactions are contained within insulated neighborhoods and 2) genetic perturbation of CTCF/cohesin-bound insulated neighborhood anchors leads to local gene dysregulation due to novel interactions outside of the neighborhood.
The majority of insulated neighborhoods appear to be maintained during development because CTCF binding and CTCF-CTCF loop structures are very similar across human cell types.[16][17] While the location of many insulated neighborhood structures are maintained across different cell types, the enhancer-gene interactions occurring within them are cell-type specific, consistent with the cell type-specific activity of enhancers.[18][19]
Association with TADs
Topologically associating domains (TADs) are megabase-size regions of relatively high DNA interaction frequencies.[20][21] Mechanistic studies indicate TADs are single insulated neighborhoods or collections of insulated neighborhoods.[22]
Relevance to human disease
Genetic and epigenetic variation of insulated neighborhood anchors have been linked to several human diseases. One study of a genetic variant linked to asthma disrupts CTCF binding and insulated neighborhood formation.[23] Studies of imprinted loci showed DNA methylation controls CTCF-anchored loops regulating gene expression. Individuals with methylation aberrations at an imprinted CTCF-binding site near IGF2/H19 form aberrant Insulated Neighborhoods and develop Beckwith-Wiedemann syndrome (when both alleles have the paternal type of insulated neighborhood) or Silver-Russell syndrome (when both alleles have the maternal type of insulated neighborhood).[24]
Insulated neighborhoods aid in identifying the target genes of disease-associated enhancer variants. The majority of disease-linked DNA variants identified from genome-wide association studies occur in enhancers.[25][26][27][28] Identifying target genes of enhancers with disease-linked variants has been difficult because enhancers may act over long distances, but the constraint on enhancer-gene targeting by insulated neighborhoods refines the prediction of target genes. For example, a DNA variant associated with type 2 diabetes occurs within an enhancer located between the CDC123 and CAMK1D genes but only affects CAMK1D because this gene and the enhancer are within the same insulated neighborhood, while CDC123 lies outside the neighborhood.[29][30]
Somatic mutations that alter insulated neighborhood anchors can contribute to tumorigenesis. Chromosomal alterations such as translocations, deletions and tandem duplications intersecting with insulated neighborhood anchor sites can activate oncogenes.[31][32][33] Epigenetic dysregulation can also contribute to tumorigenesis by altering insulated neighborhoods. IDH-mutant gliomas display altered DNA methylation patterns, so CTCF binding, which is DNA methylation-dependent, is also altered.[34] Altered CTCF-binding disrupts insulated neighborhoods and can lead to oncogene misregulation.
References
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