Prostate cancer harboring BRCA1/2 mutations are often exceptionally sensitive to PARP inhibitors. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibition. Here, we perform genome-wide CRISPR-Cas9 knockout screens in BRCA1/2-proficient prostate cancer cells and identify previously unknown genes whose loss has a profound impact on PARP inhibitor response. Specifically, MMS22L deletion, frequently observed…
Cardiac chamber-selective transcriptional programs underpin the structural and functional differences between atrial and ventricular cardiomyocytes (aCMs and vCMs). The mechanisms responsible for these chamber-selective transcriptional programs remain largely undefined. We nominated candidate chamber-selective enhancers (CSEs) by determining the genome-wide occupancy of 7 key cardiac transcription factors (GATA4, MEF2A, MEF2C, NKX2-5, SRF, TBX5, TEAD1) and transcriptional coactivator P300 in atria and…
Dr. Shiaulou Yuan's lab consists of a multidisciplinary group of biologists, biophysicists, and microscopists who aim to understand how fluid flows and biophysical forces shape the developing heart, and how these mechanisms underlie cardiac disease pathogenesis when gone awry. Specifically, they seek to illuminate how the cilium, a hair-like structure found on most cells in the human body, acts as an “antenna” to sense and translate extracellular signals into molecular processes that sculpt the early heart.
Read the Publication This week we profile a recent publication in Nature Microbiology from the lab of Dr. Yonatan Grad (pictured, back left) at Harvard and Brigham and Women’s Hospital with first author Dr. Daniel Rubin. Can you provide a brief overview of your lab’s current research focus? We study how pathogens evolve and spread, from microbial genetics through epidemic…
CRISPR-Cas gene editing has revolutionized experimental molecular biology over the past decade and holds great promise for the treatment of human genetic diseases. Here we review the development of CRISPR-Cas9/Cas12/Cas13 nucleases, DNA base editors, prime editors, and RNA base editors, focusing on the assessment and improvement of their editing precision and safety, pushing the limit of editing specificity and efficiency.…
Dr. Mariella Filbin's lab is interested in how pediatric brain tumors recapitulate certain aspects of normal brain development - what are similar behaviors and programs that are hijacked, but also what are the differences so they can target brain tumor cells specifically. Indeed, all pediatric brain tumor cells can differentiate to some degree, despite their mutations and DNA copy number variations, and thereby exit the cell cycle and no longer feed tumor growth.
Members of the tumor necrosis factor receptor superfamily (TNFRSF) are important therapeutic targets that can be activated to induce death of cancer cells or stimulate proliferation of immune cells. Although it has long been implicated that these receptors assemble preligand associated states that are required for dominant interference in human disease, such states have so far eluded structural characterization. Here,…
Since their discovery almost two decades ago, interleukin-17-producing CD4+ T cells (TH17 cells) have been implicated in the pathogenesis of multiple autoimmune and inflammatory disorders. In addition, TH17 cells have been found to play an important role in tissue homeostasis, especially in the intestinal mucosa. Recently, the use of single-cell technologies, along with fate mapping and various mutant mouse models, has…
Mammals have an inducible form of thermogenic fat, a.k.a. beige adipocytes, that is highly regulated by certain external stimuli, such as cold acclimation, cachexia, burn injury, and others. How such diverse stimuli induce beige fat biogenesis (often called the "browning" of white fat) is poorly understood. This work identified the common pathway – fat lipolysis – that is required for beige fat biogenesis in response to cold acclimation and burn injury. Specifically, lipolysis-derived linoleic acid is the major mediator that triggers the proliferation of beige fat progenitors.
Cancer prevention has a profound impact on cancer-associated mortality and morbidity. We previously identified TGFβ signaling as a candidate regulator of mammary epithelial cells associated with breast cancer risk. Here, we show that short-term TGFBR inhibitor (TGFBRi) treatment of peripubertal ACI inbred and Sprague Dawley outbred rats induces lasting changes and prevents estrogen- and carcinogen-induced mammary tumors, respectively. We identify…