Broad Institute of MIT and Harvard’s Post

While many interactions between proteins and their binding targets are as specific as a lock and key, chromatin proteins — like transcription factors (TFs) and coregulators — contain intrinsically disordered regions (IDRs) that allow some leeway in the partners they bind with. In Molecular Cell, Amanda Waterbury, Ph.D., Hui Si Kwok, and Ceejay Lee in Brian Liau 's lab; Malvina Papanastasiou, Shaunak Raval, and Steven Carr in the Proteomics Platform; and colleagues describe how the IDR of one coregulator, LSD1, has the opposite effect: It imparts specificity by insulating LSD1's structured domain from indiscriminate TF association. Mutations in LSD1's IDR break this insulation, leading to aberrant LSD1-TF association, enhancer dysregulation, and drug resistance in leukemia. https://lnkd.in/d8-JR-Zk #BroadInstitute #Science #ScienceNews #Research #ScientificResearch

Velcrins are "molecular glues," compounds that induce proteins that don't typically bind to one another to interact. Most molecular glues are used to trigger degradation of their targets, but velcrins instead spark a unique form of cell death — tomoptosis, marked by digestion of a specific tRNA and total shutdown of protein production within a cell — by forcing the proteins PDE3A and SLFN12 to stick together, activating the SLFN12 tRNase. In a Cell Chemical Biology Commentary, Heidi Greulich presents what's known about velcrins, describes open questions regarding the PDE3A-SLFN12 complex, SLFN12 function, and velcrin therapeutic potential, and suggests new ways to leverage SLFN12 for cancer therapy. #BroadInstitute #Science #ScienceNews #Research #ScientificResearch

To better support research of underrepresented populations, Zan Koenig, Mary Yohannes, Alicia Martin, and colleagues produced a new easily accessible resource that includes a set of high-quality genomes of diverse ancestry. The team jointly called variants from more than 4,000 whole genomes from 80 populations in the Human Genome Diversity Project and 1000 Genomes Project using data from gnomAD, resulting in 153 million single-nucleotide variants, indels, and structural variants. They performed a detailed ancestry analysis of the data set, demonstrated its improvements over prior versions, and offered tutorials for users of the new resource. Read more in Genome Research. https://lnkd.in/dW5Qrpnw #BroadInstitute #Science #ScienceNews #Research #ScientificResearch

Women face greater risk from cardiovascular disease than men for reasons that aren’t fully understood, and existing polygenic scores to predict risk perform worse in women than in men. Kaavya Paruchuri, Pradeep Natarajan, and colleagues built a new polygenic score that incorporates alleles exhibiting differential effects on risk for women than men. Using data from the CARDIoGRAMplusC4D analysis, their score helped improve prediction among women younger than 55, with some sex-based disparities still present. The work underscores the ongoing need to bridge the performance gap in polygenic risk prediction for coronary artery disease. Read more in the Journal of the American Heart Association. #BroadInstitute #Science #ScienceNews #Research #ScientificResearch

Researchers at Whitehead Institute and Broad have developed a gene-silencing tool, CHARM, that turns off the gene causing prion diseases and could pave the way for new gene therapies for these fatal conditions. In mice, the epigenetic editing technology eliminated more than 80% of the prion protein in the brain. Read more about the journey from research to potential therapy. #BroadInstitute #Science #ScienceNews #Research #ScientificResearch

The risk of coronary artery disease (CAD) can change over a person’s lifetime, and current methods of estimating CAD risk don’t incorporate new information over time. Sarah Urbut, Pradeep Natarajan, and colleagues have developed MSGene, a model that accounts for longitudinal data, clinical covariates, and CAD polygenic risk scores to estimate transitions between 10 cardiometabolic states. The team used MSGene to analyze longitudinal data from more than 480,000 UK Biobank participants and found that it improved risk predictions compared to other risk scores. The findings, in Nature Communications, highlight the potential public health value of more accurate lifetime CAD risk estimation. #BroadInstitute #Science #ScienceNews #Research #ScientificResearch

Research over the last decade has found links between the gut microbiome and risk for type 2 diabetes, which affects half a billion people worldwide. In the largest and most diverse study yet of the microbiome and type 2 diabetes, a Brigham and Women's Hospital, Harvard T.H. Chan School of Public Health, and Broad team found that the presence of specific viruses and genetic variants within bacteria correspond with T2D risk. #Microbiome #T2D #Type2Diabetes #Type2DiabetesResearch #BroadInstitute #Science #ScienceNews #Research #ScientificResearch

Fewer than one percent of people who get the flu every year get tested in part because most tests require trained personnel and expensive equipment. Now researchers have developed a low-cost paper strip test that could allow more patients to find out which type of flu they have and get the right treatment. The test uses CRISPR to distinguish between the two main types of seasonal flu (influenza A and B) as well as seasonal flu subtypes and can identify strains that resist antiviral treatment. With further work, it could potentially detect swine and avian flu strains, including H5N1, currently infecting cattle. #BroadInstitute #Science #ScienceNews #Research #ScientificResearch #CRISPR #CRISPRResearch

About half of cancer patients treated with chimeric antigen receptor (CAR) T cell therapy do not respond to treatment, or relapse after treatment because of tumor resistance to apoptosis or poor CAR T cell persistence. To address this, Felix Korell, Tony Letai, Marcela Maus, and colleagues developed CAR T cells that overexpressed different proteins from the Bcl-2 family, which are known to protect cells against apoptosis. They found that overexpressing the Bcl-xL protein improved CAR T cell persistence and function in mouse models of lymphoma and leukemia, suggesting strategies for improving CAR T cell therapies alone and in combination with other cancer therapeutics. Read more in Science Translational Medicine. #BroadInstitute #Science #ScienceNews #Research #ScientificResearch