Phillip A. Sharp
Massachusetts Institute of Technology
Publications 527
#1Amanda Joy Whipple (MIT: Massachusetts Institute of Technology)
#2Vincent Breton-Provencher (Picower Institute for Learning and Memory)H-Index: 4
Last.Phillip A. Sharp (MIT: Massachusetts Institute of Technology)H-Index: 139
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Summary Imprinted genes with parental-biased allelic expression are frequently co-regulated and enriched in common biological pathways. Here, we functionally characterize a large cluster of microRNAs (miRNAs) expressed from the maternally inherited allele (“maternally expressed”) to explore the molecular and cellular consequences of imprinted miRNA activity. Using an induced neuron (iN) culture system, we show that maternally expressed miRNAs from the miR-379/410 cluster direct the RNA-induced s...
#1Megan L. Insco (Harvard University)
#2Brian J. Abraham (St. Jude Children's Research Hospital)H-Index: 24
Last.Leonard I. Zon (HHMI: Howard Hughes Medical Institute)H-Index: 118
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Transcriptional Cyclin Dependent Kinases modulate RNA Polymerase II function to impact gene expression. Here, we show that CDK13 is mutated in 4% of patient melanomas and mutation or downregulation is associated with poor overall survival. Mutant CDK13 lacks kinase activity and overexpression in zebrafish leads to accelerated melanoma. CDK13 mutant fish and human melanomas accumulate prematurely terminated RNAs that are translated into truncated proteins. CDK13 binds to and regulates the phospho...
#1Timothy J. KellyH-Index: 1
#2Hiroshi I. SuzukiH-Index: 19
Last.Phillip A. SharpH-Index: 139
view all 5 authors...
#1Krishna Shrinivas (MIT: Massachusetts Institute of Technology)H-Index: 5
#2Benjamin R. Sabari (MIT: Massachusetts Institute of Technology)H-Index: 9
Last.Arup K. ChakrabortyH-Index: 54
view all 11 authors...
Summary Enhancers are DNA elements that are bound by transcription factors (TFs), which recruit coactivators and the transcriptional machinery to genes. Phase-separated condensates of TFs and coactivators have been implicated in assembling the transcription machinery at particular enhancers, yet the role of DNA sequence in this process has not been explored. We show that DNA sequences encoding TF binding site number, density, and affinity above sharply defined thresholds drive condensation of TF...
15 CitationsSource
#1Yang Eric Guo (MIT: Massachusetts Institute of Technology)H-Index: 8
#2John C. Manteiga (MIT: Massachusetts Institute of Technology)H-Index: 4
Last.Richard A. Young (MIT: Massachusetts Institute of Technology)H-Index: 143
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The synthesis of pre-mRNA by RNA polymerase II (Pol II) involves the formation of a transcription initiation complex, and a transition to an elongation complex1–4. The large subunit of Pol II contains an intrinsically disordered C-terminal domain that is phosphorylated by cyclin-dependent kinases during the transition from initiation to elongation, thus influencing the interaction of the C-terminal domain with different components of the initiation or the RNA-splicing apparatus5,6. Recent observ...
17 CitationsSource
#1Amanda Joy Whipple (Harvard University)
Last.Phillip A. Sharp (MIT: Massachusetts Institute of Technology)H-Index: 139
view all 5 authors...
Imprinted genes with parental-biased expression are hypothesized to result from an evolutionary conflict between the parental genomes over procurement of maternal resources. Accordingly, imprinted genes are enriched in pathways regulating nutrient acquisition, energy homeostasis, and growth. Here, we functionally characterize a large cluster of maternally-expressed microRNAs (miRNAs) to explore why they evolved imprinted expression in neurons. Using an induced neuron (iN) culture system, we show...
#1Meenakshi Chakraborty (MIT: Massachusetts Institute of Technology)
#2Sofia Hu (MIT: Massachusetts Institute of Technology)
Last.Salil Garg (MIT: Massachusetts Institute of Technology)H-Index: 9
view all 7 authors...
Cell-to-cell variation in gene expression is a common feature of developmental processes. Yet, it remains unclear whether molecular mediators can generate variation and how this process is coordinated across loci to allow the emergence of new cell states. Using embryonic stem cells (ESCs) as a model of development, we found interconverting cell states that resemble developmental expression programs and vary in activity at specific enhancers, such as those regulating pluripotency genes Nanog and ...
#1Giedre Grigelioniene (KI: Karolinska Institutet)H-Index: 18
#2Hiroshi I. Suzuki (MIT: Massachusetts Institute of Technology)H-Index: 19
Last.Tatsuya Kobayashi (Harvard University)H-Index: 35
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MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Heterozygous loss-of-function point mutations of miRNA genes are associated with several human congenital disorders1–5, but neomorphic (gain-of-new-function) mutations in miRNAs due to nucleotide substitutions have not been reported. Here we describe a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skele...
6 CitationsSource
#2Phillip A. SharpH-Index: 139
view all 3 authors...