Transcriptional elongation checkpoint control in development and disease

Smith, Edwin R.; Shilatifard, Ali

doi:10.1101/gad.215137.113

Cited by 65 publications

(57 citation statements)

References 95 publications

(140 reference statements)

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“…Given the fact that the misregulation of the elongation stage of transcription has been associated with human diseases, including cancer (Smith and Shilatifard 2013), the use of TPL for the in vivo study of transcriptional elongation control should be very informative.…”

Section: Discussionmentioning

confidence: 99%

“…Promoter-proximal paused Pol II is prevalent in metazoans, particularly at genes related to developmental and environmental pathways (Core and Lis 2008;Adelman and Lis 2012;Smith and Shilatifard 2013). In Drosophila, it has been shown that minimal promoter elements with paused Pol II are sufficient to mediate a synchronous pattern of gene expression during development (Lagha et al 2013).…”

mentioning

confidence: 99%

“…Numerous studies have revealed that transcription by RNA polymerase II (Pol II) is intricately regulated at multiple steps (Hsin and Manley 2012;Kwak and Lis 2013;Smith and Shilatifard 2013). Pol II is recruited to promoters with general transcription factors (GTFs), and starts transcription initiation by synthesizing ;20-to 60-nucleotide (nt) RNAs (Rasmussen and Lis 1993).…”

mentioning

confidence: 99%

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Stably paused genes revealed through inhibition of transcription initiation by the TFIIH inhibitor triptolide

2015

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Transcription by RNA polymerase II (Pol II) in metazoans is regulated in several steps, including preinitiation complex (PIC) formation, initiation, Pol II escape, productive elongation, cotranscriptional RNA processing, and termination. Genome-wide studies have demonstrated that the phenomenon of promoter-bound Pol II pausing is widespread, especially for genes involved in developmental and stimulus-responsive pathways. However, a mechanistic understanding of the paused Pol II state at promoters is limited. For example, at a global level, it is unclear to what extent the engaged paused Pol II is stably tethered to the promoter or undergoes rapid cycles of initiation and termination. Here we used the small molecule triptolide (TPL), an XPB/TFIIH inhibitor, to block transcriptional initiation and then measured Pol II occupancy by chromatin immunoprecipitation (ChIP) followed by next-generation sequencing (ChIP-seq). This inhibition of initiation enabled us to investigate different states of paused Pol II. Specifically, our global analysis revealed that most genes with paused Pol II, as defined by a pausing index, show significant clearance of Pol II during the period of TPL treatment. Our study further identified a group of genes with unexpectedly stably paused Pol II, with unchanged Pol II occupancy even after 1 h of inhibition of initiation. This group of genes constitutes a small portion of all paused genes defined by the conventional criterion of pausing index. These findings could pave the way for evaluating the contribution of different elongation/pausing factors on different states of Pol II pausing in developmental and other stimulus-responsive pathways.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Stably paused genes revealed through inhibition of transcription initiation by the TFIIH inhibitor triptolide

2015

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“…(D) Therapeutic targeting of MLL translocated leukemia. MLL chimeras recruit SEC and/or DotCom to MLL target genes, which leads to their aberrant activation through misregulation of the transcriptional elongation checkpoint (Smith and Shilatifard 2013). Multiple therapeutic strategies have been developed to target different steps required for the activation of MLL chimera target genes in leukemia: MI503 blocks the association of Menin with MLL, potentially affecting recruitment of the MLL chimera to chromatin (indicated by a question mark); flavopiridol (FP) inhibits the kinase activity of SEC subunit P-TEFb; and EPZ-5676 is a small molecule blocking the enzymatic activity of DOT1L.…”

Section: Mll In Normal Hematopoiesis and In The Transcriptional Elongmentioning

confidence: 99%

Epigenetics of hematopoiesis and hematological malignancies

Hu¹,

Shilatifard

2016

Genes Dev.

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Hematological malignancies comprise a diverse set of lymphoid and myeloid neoplasms in which normal hematopoiesis has gone awry and together account for ∼10% of all new cancer cases diagnosed in the United States in 2016. Recent intensive genomic sequencing of hematopoietic malignancies has identified recurrent mutations in genes that encode regulators of chromatin structure and function, highlighting the central role that aberrant epigenetic regulation plays in the pathogenesis of these neoplasms. Deciphering the molecular mechanisms for how alterations in epigenetic modifiers, specifically histone and DNA methylases and demethylases, drive hematopoietic cancer could provide new avenues for developing novel targeted epigenetic therapies for treating hematological malignancies. Just as past studies of blood cancers led to pioneering discoveries relevant to other cancers, determining the contribution of epigenetic modifiers in hematologic cancers could also have a broader impact on our understanding of the pathogenesis of solid tumors in which these factors are mutated.

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“…2,48 Characterization of the structure and function of this novel transcription elongation checkpoint will provide new insights into regulation of gene expression at the level of transcription elongation and how this might be misregulated in human disease.…”

Section: Future Prospectsmentioning

confidence: 99%