Histone H3R17me2a mark recruits human RNA Polymerase-Associated Factor 1 Complex to activate transcription

Wu, Jianpeng; Xu, Wei

doi:10.1073/pnas.1114905109

Cited by 76 publications

(65 citation statements)

References 38 publications

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“…In these cells, Ctr9 protein was undetectable by Western blot (Supplemental Fig. S5A, lanes 1-3), and expression of the other four subunits in hPAFc was significantly reduced, consistent with the previous reports (Youn et al 2007;Wu and Xu 2012). Similar to the inducible Ctr9 knockdown, stable Ctr9 knockdown in MCF7 cells also triggered dramatic morphological changes (Supplemental .…”

Section: Resultssupporting

confidence: 77%

“…To assess the functional roles of Ctr9 in ERα + breast cancer, Ctr9 expression was knocked down in MCF7 breast cancer cells using a previously established cell line model in which Ctr9 expression is turned down in the presence of doxycycline (Dox) (i.e., MCF7-tet-on-shCtr9) (Wu and Xu 2012). As shown in Figure 2, A and B, Dox treatment led to partial loss of Ctr9 after 3 d and almost complete loss after 5 or 9 d. Interestingly, the Ctr9 knockdown cells adopted an elongated and enlarged shape after 5 or 9 d of treatment with Dox ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Future proteomic studies of Ctr9-interacting proteins in MCF7 cells could provide insight into the mechanisms by which Ctr9 drives ERα + breast carcinogenesis. Nonetheless, we cannot rule out the possibility that intact hPAFc is required at some level for the full impact of Ctr9 in ERα + breast cancer because knockdown of Ctr9 at least partially suppresses expression of all PAFc subunits (this study) and disrupts the integrity of PAFc (Wu and Xu 2012). ChIP-seq (ChIP combined with deep sequencing) analyses of all of the PAFc subunits will help clarify the dependence or independence of PAFc subunits in the context of the ERα regulatory network.…”

Section: Discussionmentioning

confidence: 99%

“…PAFc is evolutionarily conserved from yeast to Drosophila and humans; however, the hPAFc differs from yeast PAFc in one subunit: Ski8 (also known as WDR61) in humans and Rtf1 in yeast. As a multisubunit complex, the protein stability of each subunit is closely interrelated and regulated by the complex stoichiometry, as deficiency in one subunit can destabilize one or more of the other subunits in both yeast PAFc and hPAFc (Mueller et al 2004;Lin et al 2008;Wu and Xu 2012). Moreover, structural and biochemical evidence shows that Paf1 and Leo1 form a heterodimer and that Ctr9 acts as a key scaffold protein during hPAFc assembly (Chu et al 2013).…”

mentioning

confidence: 99%

“…Coactivator-associated arginine methyltransferase 1 (CARM1) is a potent coactivator of ERα, which specifically deposits the active histone mark H3R17me2a (Chen et al 1999;Al-Dhaheri et al 2011) near the promoter of target genes. We previously showed that the human RNA polymerase II (RNAPII)-associated factor complex (hPAFc) interacts directly with H3R17me2a and that this association is required for productive transcriptional initiation and elongation of the pS2 gene in MCF7 breast cancer cells (Wu and Xu 2012).…”

mentioning

confidence: 99%

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Ctr9, a key subunit of PAFc, affects global estrogen signaling and drives ERα-positive breast tumorigenesis

Zeng

2015

Genes Dev.

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The human RNA polymerase II (RNAPII)-associated factor complex (hPAFc) and its individual subunits have been implicated in human diseases, including cancer. However, its involvement in breast cancer awaits investigation. Using data mining and human breast cancer tissue microarrays, we found that Ctr9, the key scaffold subunit in hPAFc, is highly expressed in estrogen receptor α-positive (ERα + ) luminal breast cancer, and the high expression of Ctr9 correlates with poor prognosis. Knockdown of Ctr9 in ERα + breast cancer cells almost completely erased estrogen-regulated transcriptional response. At the molecular level, Ctr9 enhances ERα protein stability, promotes recruitment of ERα and RNAPII, and stimulates transcription elongation and transcription-coupled histone modifications. Knockdown of Ctr9, but not other hPAFc subunits, alters the morphology, proliferative capacity, and tamoxifen sensitivity of ERα + breast cancer cells. Together, our study reveals that Ctr9, a key subunit of hPAFc, is a central regulator of estrogen signaling that drives ERα + breast tumorigenesis, rendering it a potential target for the treatment of ERα + breast cancer.

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Section: Resultssupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Ctr9, a key subunit of PAFc, affects global estrogen signaling and drives ERα-positive breast tumorigenesis

Zeng

2015

Genes Dev.

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Identification and in silico structural analysis of Gallus gallus protein arginine methyltransferase 4 (PRMT4)

et al. 2017

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Protein arginine methyltransferase 4 ( PRMT 4) is an essential epigenetic regulator of fundamental and conserved processes during vertebrate development, such as pluripotency and differentiation. Surprisingly, PRMT 4 homologs have been identified in nearly all vertebrate classes except the avian genome. This raises the possibility that in birds PRMT 4 functions are taken over by other PRMT family members. Here, we reveal the existence of a bona fide PRMT 4 homolog in the chicken, Gallus gallus . Using a biochemical approach, we initially purified a putative chicken PRMT 4 protein and thus provided the first evidence for the presence of an endogenous PRMT 4‐specific enzymatic activity toward histone H3 arginine 17 (H3R17) in avian cells. We then isolated a G. gallus PRMT 4 (gg PRMT 4 ) transcript encompassing the complete open reading frame. Recombinant gg PRMT 4 possesses intrinsic methyltransferase activity toward H3R17. CRISPR /Cas9‐mediated deletion of gg PRMT 4 demonstrated that the transcript identified here encodes avian PRMT 4. Combining protein–protein docking and homology modeling based on published crystal structures of murine PRMT 4, we found a strong structural similarity of the catalytic core domain between chicken and mammalian PRMT 4. Strikingly, in silico structural comparison of the N‐terminal Pleckstrin homology ( PH ) domain of avian and murine PRMT 4 identified strictly conserved amino acids that are involved in an interaction interface toward the catalytic core domain, facilitating for the first time a prediction of the relative spatial arrangement of these two domains. Our novel findings are particularly exciting in light of the essential function of the PH domain in substrate recognition and methylation by PRMT 4.

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Switches in histone modifications epigenetically control vitamin D3‐dependent transcriptional upregulation of the CYP24A1 gene in osteoblastic cells

Moena

Merino

Lian

et al. 2019

Journal Cellular Physiology

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In bone cells vitamin D dependent regulation of gene expression principally occurs through modulation of gene transcription. Binding of the active vitamin D metabolite, 1,25‐dihydroxy vitamin D3 (1,25(OH)2D3) to the vitamin D receptor (VDR) induces conformational changes in its C‐terminal domain enabling competency for interaction with physiologically relevant coactivators, including SRC‐1. Consequently, regulatory complexes can be assembled that support intrinsic enzymatic activities with competency to posttranslationally modify chromatin histones at target genomic sequences to epigenetically alter transcription. Here we examine specific transitions in representation and/or enrichment of epigenetic histone marks during 1,25(OH)2D3 mediated upregulation of CYP24A1 gene expression in osteoblastic cells. This gene encodes the 24‐hydroxylase enzyme, essential for biological control of vitamin D levels. We demonstrate that as the CYP24A1 gene promoter remains transcriptionally silent, there is enrichment of H4R3me2s together with its “writing” enzyme PRMT5 and decreased abundance of the istone H3 and H4 acetylation, H3R17me2a, and H4R3me2a marks as well as of their corresponding “writers.” Exposure of osteoblastic cells to 1,25(OH)2D3 stimulates the recruitment of a VDR/SRC‐1 containing complex to the CYP24A1 promoter to mediate increased H3/H4 acetylation. VDR/SRC‐1 binding occurs concomitant with the release of PRMT5 and the recruitment of the arginine methyltransferases CARM1 and PRMT1 to catalyze the deposition of the H3R17me2a and H4R3me2a marks, respectively. Our results indicate that these dynamic transitions of histone marks at the CYP24A1 promoter, provide a “chromatin context” that is transcriptionally competent for activation of the CYP24A1 gene in osteoblastic cells in response to 1,25(OH)2D3.

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Histone H3R17me2a mark recruits human RNA Polymerase-Associated Factor 1 Complex to activate transcription

Cited by 76 publications

References 38 publications

Ctr9, a key subunit of PAFc, affects global estrogen signaling and drives ERα-positive breast tumorigenesis

Ctr9, a key subunit of PAFc, affects global estrogen signaling and drives ERα-positive breast tumorigenesis

Identification and in silico structural analysis of Gallus gallus protein arginine methyltransferase 4 (PRMT4)

Switches in histone modifications epigenetically control vitamin D3‐dependent transcriptional upregulation of the CYP24A1 gene in osteoblastic cells

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