Shilatifard Laboratory
Recent Videos from the Shilatifard Lab
Transcriptional elongation control of hypoxic response
A recent publication in PNAS from the Simpson Querrey Institute for Epigenetics in the Shilatifard Laboratory identified the CDK9 complex required for transcriptional response to hypoxia. New findings on the relationship between CDK9, BRD4, and PAF1C provide insight into therapeutically targetable mechanisms that regulate the pause-release of RNA Polymerase II in hypoxia-driven diseases.
Localized Genetic Mutations May Serve as Biomarker for Wide Range of Cancers
A recent publication in PNAS from the Simpson Querrey Institute for Epigenetics in the Shilatifard Laboratory discovered that unique amino acid sequence properties and biological functions of mutated MLL4 contribute to the high prevalence of KMT2D mutation rate. Mutant KMT2D transcripts can actually evade nonsense mRNA decay. Instead, these transcripts are expressed as truncated proteins that localize to the cytosol, rather than the nucleus. This finding suggests that MLL4 could potentially be used as a biomarker for prognosis and patient stratification based on predicted sensitivity to targeted therapies.
ELOA3: Primate-specific RNA polymerase II elongation factor encoded by a tandem repeat gene cluster
A recent publication in Science Advances from the Simpson Querrey Institute for Epigenetics in the Shilatifard Laboratory demonstrates the ELOA3 gene cluster is conserved among primates and the number of ELOA3 gene repeats is variable in the human population and across primate species. Moreover, the ELOA3 gene cluster has undergone concerted evolution and homogenization within primates. Future studies could lead to the creation of sensitivity in cell lines through the understanding of ELOA3 activation.
Exploring Transcription Elongation Control in Development, Disease and Aging
A recent publication in Molecular Cell from the Simpson Querrey Institute for Epigenetics in the Shilatifard Laboratory reviews the essential role of RNA Polymerase II elongation. Since the discovery of the elongation factor ELL in translocation induced leukemia, transcriptional elongation by Pol II is considered a critical regulatory step in gene expression and dysregulation has been linked to the mechanisms underlying human disease and aging.
Distinct layers of BRD4-PTEFb reveal bromodomain-independent function in transcriptional regulation
A recent publication in Molecular Cell from the Simpson Querrey Institute for Epigenetics demonstrates the dispensability of BRD4’s BET bromodomains, which bind acetylated histones and are targeted by inhibitors such as JQ1, for the release of paused Pol II. A bromodomain-less, C-terminal fragment of BRD4 is instead both necessary and sufficient to drive Pol II pause release.
Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations
A recent publication in JCI from the Simpson Querrey Institute for Epigenetics revealed an intimate interplay between epigenetic regulation of gene expression and metabolism and its alteration. This study provides possible treatment strategies of diseases associated with MLL3 and MLL4 loss-of-function mutations and depicts a metabolic dependency map in cells that loose MLL3 and MLL4 expression.
Enhancing HIV-1 latency reversal through regulating the elongating RNA Pol II pause-release by a small-molecule disruptor of PAF1C
A recent publication in Science Advances from the Simpson Querrey Institute for Epigenetics describes the regulation of paused RNA Polymerase II in HIV latency reversal and the discovery of a possible small molecule disruptor in this process.
SPT6 Functions in Transcriptional Pause/Release via PAF1C Recruitment
A recent publication in Molecular Cell from the Simpson Querrey Institute for Epigenetics describes new understandings of the RNA polymerase II elongation complex. SPT6 recruits the PAF1 complex and removes NELF in order for RNA polymerase II to be released.
Transcription Elongation Checkpoint Discovered
A recent publication in Molecular Cell from the Simpson Querrey Institute for Epigenetics describes how the loss of SPT5 from RNA polymerase II, results in the degradation of the largest subunit RPB1. These findings provide insight into productive elongation and how the misregulation of SPT5 is associated with human diseases.
Epigenetic Targeted Therapy of Gene Expression in Leukemic Cells
A recent publication in Nature Cancer from the Simpson Querrey Institute for Epigenetics that describes the effects of ASXL1 mutations in BAP1 and the role it plays in leukemic pathogenesis. As well as the discovery of an inhibitor that could help.
Uncoupling Histone H3K4 trimethylation from transcription
A recent publication in Nature Genetics from the Simpson Querrey Institute for Epigenetics describes the balance between COMPASS, PRC2, and DNA methylation. This discovery disentangles Histone H3 K4 trimethylation from transcription and reveals how these players work in concert to dictate transcriptional decisions.
Balancing Regulation of Gene Expression in Cancer
Mutations in the COMPASS and Polycomb families of chromatin modifiers have been identified that disrupt the balanced regulation of gene expression (Wang et al., Nature Medicine 2018) (Piunti & Shilatifard, Science 2016). Researchers have discovered mechanisms to restore expression of tumor suppressor genes in several cancers, including bladder cancer, which are being evaluated in ongoing clinical trials.
Epigenetics and Cancer with Ali Shilatifard
Northwestern University Feinberg School of Medicine's Breakthroughs Podcast features Ali Shilatifard.
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What We Do
The regulation of gene expression by RNA polymerase II is essential for development and differentiation, and its misregulation contributes to the pathogenesis of many forms of cancers. The goal of our laboratory is to define the molecular mechanisms underlying cancer pathogenesis and to identify potential targets for therapy. These studies have been done through detailed understanding of proteins and protein complexes that regulate chromatin modifications, transcriptional initiation, and transcriptional elongation. Several of such findings from our lab are now under clinical studies for the treatment of bladder cancer and pediatric brain tumors.
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