DBC1, p300, HDAC3, and Siah1 coordinately regulate ELL stability and function for expression of its target genes
Among all of the Super Elongation Complex (SEC) components, ELL1 (also known as ELL) is the only bona fide elongation factor that directly stimulates transcription elongation by RNA polymerase II. However, the mechanism(s) of functional regulation of ELL1 (referred to as ELL hereafter), through its...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2020-03, Vol.117 (12), p.6509-6520 |
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| creator | Basu, Subham Barad, Mahesh Yadav, Dipika Nandy, Arijit Mukherjee, Bidisha Sarkar, Jit Chakrabarti, Partha Mukhopadhyay, Satinath Biswas, Debabrata |
| description | Among all of the Super Elongation Complex (SEC) components, ELL1 (also known as ELL) is the only bona fide elongation factor that directly stimulates transcription elongation by RNA polymerase II. However, the mechanism(s) of functional regulation of ELL1 (referred to as ELL hereafter), through its stabilization, is completely unknown. Here, we report a function of human DBC1 in regulating ELL stability involving HDAC3, p300, and Siah1. Mechanistically, we show that p300-mediated site-specific acetylation increases, whereas HDAC3-mediated deacetylation decreases, ELL stability through polyubiquitylation by the E3 ubiquitin ligase Siah1. DBC1 competes with HDAC3 for the same binding sites on ELL and thus increases its acetylation and stability. Knockdown of DBC1 reduces ELL levels and expression of a significant number of genes, including those involved in glucose metabolism. Consistently, Type 2 diabetes patient-derived peripheral blood mononuclear cells show reduced expression of DBC1 and ELL and associated key target genes required for glucose homeostasis. Thus, we describe a pathway of regulating stability and functions of key elongation factor ELL for expression of diverse sets of genes, including ones that are linked to Type 2 diabetes pathogenesis. |
| doi_str_mv | 10.1073/pnas.1912375117 |
| format | Article |
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However, the mechanism(s) of functional regulation of ELL1 (referred to as ELL hereafter), through its stabilization, is completely unknown. Here, we report a function of human DBC1 in regulating ELL stability involving HDAC3, p300, and Siah1. Mechanistically, we show that p300-mediated site-specific acetylation increases, whereas HDAC3-mediated deacetylation decreases, ELL stability through polyubiquitylation by the E3 ubiquitin ligase Siah1. DBC1 competes with HDAC3 for the same binding sites on ELL and thus increases its acetylation and stability. Knockdown of DBC1 reduces ELL levels and expression of a significant number of genes, including those involved in glucose metabolism. Consistently, Type 2 diabetes patient-derived peripheral blood mononuclear cells show reduced expression of DBC1 and ELL and associated key target genes required for glucose homeostasis. Thus, we describe a pathway of regulating stability and functions of key elongation factor ELL for expression of diverse sets of genes, including ones that are linked to Type 2 diabetes pathogenesis.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1912375117</identifier><identifier>PMID: 32152128</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Acetylation ; Binding sites ; Biological Sciences ; Deacetylation ; Diabetes ; Diabetes mellitus (non-insulin dependent) ; DNA-directed RNA polymerase ; Elongation ; Event-related potentials ; Gene expression ; Genes ; Glucose ; Glucose metabolism ; Homeostasis ; Leukocytes (mononuclear) ; Pathogenesis ; Peripheral blood mononuclear cells ; RNA polymerase ; RNA polymerase II ; Stability ; Ubiquitin ; Ubiquitin-protein ligase</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2020-03, Vol.117 (12), p.6509-6520</ispartof><rights>Copyright © 2020 the Author(s). Published by PNAS.</rights><rights>Copyright National Academy of Sciences Mar 24, 2020</rights><rights>Copyright © 2020 the Author(s). 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However, the mechanism(s) of functional regulation of ELL1 (referred to as ELL hereafter), through its stabilization, is completely unknown. Here, we report a function of human DBC1 in regulating ELL stability involving HDAC3, p300, and Siah1. Mechanistically, we show that p300-mediated site-specific acetylation increases, whereas HDAC3-mediated deacetylation decreases, ELL stability through polyubiquitylation by the E3 ubiquitin ligase Siah1. DBC1 competes with HDAC3 for the same binding sites on ELL and thus increases its acetylation and stability. Knockdown of DBC1 reduces ELL levels and expression of a significant number of genes, including those involved in glucose metabolism. Consistently, Type 2 diabetes patient-derived peripheral blood mononuclear cells show reduced expression of DBC1 and ELL and associated key target genes required for glucose homeostasis. Thus, we describe a pathway of regulating stability and functions of key elongation factor ELL for expression of diverse sets of genes, including ones that are linked to Type 2 diabetes pathogenesis.</description><subject>Acetylation</subject><subject>Binding sites</subject><subject>Biological Sciences</subject><subject>Deacetylation</subject><subject>Diabetes</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>DNA-directed RNA polymerase</subject><subject>Elongation</subject><subject>Event-related potentials</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Glucose</subject><subject>Glucose metabolism</subject><subject>Homeostasis</subject><subject>Leukocytes (mononuclear)</subject><subject>Pathogenesis</subject><subject>Peripheral blood mononuclear cells</subject><subject>RNA polymerase</subject><subject>RNA polymerase II</subject><subject>Stability</subject><subject>Ubiquitin</subject><subject>Ubiquitin-protein ligase</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNpdkU1vEzEQhlcIREPhzAlkiQuHpB1_rXcvlUpaKFIkDsDZ8nrt1NHGXmwvIv8eLynh4-Sx55nXM_NW1UsMFxgEvRy9She4xYQKjrF4VC0wtHhVsxYeVwsAIlYNI-ysepbSDgBa3sDT6owSzAkmzaIab96t8RKNFGCJ7m6u13SJlO_RZ6fuMdIhxN55lc1wQNFsp6GE6HazQSmrzg0uH37RdvI6u-CRDRGZH2M0Kc3XYJHLCWUVtyajrfEmPa-eWDUk8-LhPK--vr_9sr5bbT59-Li-3qw0YzSXrkXDGNQWKDcd76ntTKexYUbrnmkqGLWaGsuhqaHuO84EcNtRKG9aWErPq6uj7jh1e9Nr43NUgxyj26t4kEE5-W_Gu3u5Dd-lwFA-FkXg7YNADN8mk7Lcu6TNMChvwpTkvPIW5r0X9M1_6C5M0ZfxCtVQTggWbaEuj5SOIaVo7KkZDHJ2U85uyj9ulorXf89w4n_bV4BXR2CXcoinPKlb0vJa0J9KT6RK</recordid><startdate>20200324</startdate><enddate>20200324</enddate><creator>Basu, Subham</creator><creator>Barad, Mahesh</creator><creator>Yadav, Dipika</creator><creator>Nandy, Arijit</creator><creator>Mukherjee, Bidisha</creator><creator>Sarkar, Jit</creator><creator>Chakrabarti, Partha</creator><creator>Mukhopadhyay, Satinath</creator><creator>Biswas, Debabrata</creator><general>National Academy of Sciences</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20200324</creationdate><title>DBC1, p300, HDAC3, and Siah1 coordinately regulate ELL stability and function for expression of its target genes</title><author>Basu, Subham ; 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| subjects | Acetylation Binding sites Biological Sciences Deacetylation Diabetes Diabetes mellitus (non-insulin dependent) DNA-directed RNA polymerase Elongation Event-related potentials Gene expression Genes Glucose Glucose metabolism Homeostasis Leukocytes (mononuclear) Pathogenesis Peripheral blood mononuclear cells RNA polymerase RNA polymerase II Stability Ubiquitin Ubiquitin-protein ligase |
| title | DBC1, p300, HDAC3, and Siah1 coordinately regulate ELL stability and function for expression of its target genes |
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