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SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia
Histone methyltransferase SETD1A is critical for acute myeloid leukemia (AML) cell survival, but the molecular mechanism driving SETD1A gene regulation remains elusive. To delineate the role of SETD1A, we utilize a protein degrader technology to induce rapid SETD1A degradation in AML cell lines. SET...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9771694/ https://www.ncbi.nlm.nih.gov/pubmed/36450243 http://dx.doi.org/10.1016/j.celrep.2022.111727 |
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author | Hoshii, Takayuki Perlee, Sarah Kikuchi, Sota Rahmutulla, Bahityar Fukuyo, Masaki Masuda, Takeshi Ohtsuki, Sumio Soga, Tomoyoshi Nabet, Behnam Kaneda, Atsushi |
author_facet | Hoshii, Takayuki Perlee, Sarah Kikuchi, Sota Rahmutulla, Bahityar Fukuyo, Masaki Masuda, Takeshi Ohtsuki, Sumio Soga, Tomoyoshi Nabet, Behnam Kaneda, Atsushi |
author_sort | Hoshii, Takayuki |
collection | PubMed |
description | Histone methyltransferase SETD1A is critical for acute myeloid leukemia (AML) cell survival, but the molecular mechanism driving SETD1A gene regulation remains elusive. To delineate the role of SETD1A, we utilize a protein degrader technology to induce rapid SETD1A degradation in AML cell lines. SETD1A degradation results in immediate downregulation of transcripts associated with DNA repair and heme biosynthesis pathways. CRISPR-based functional analyses and metabolomics reveal an essential role of SETD1A to maintain mitochondrial respiration in AML cells. These SETD1A targets are enriched in head-to-head (H2H) genes. SETD1A degradation disrupts a non-enzymatic SETD1A domain-dependent cyclin K function, increases the Ser5P RNA polymerase II (RNAPII) at the transcriptional start site (TSS), and induces the promoter-proximal pausing of RNAPII in a strand-specific manner. This study reveals a non-enzymatic role for SETD1A in transcriptional pause release and provides insight into the mechanism of RNAPII pausing and its function in cancer. |
format | Online Article Text |
id | pubmed-9771694 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
record_format | MEDLINE/PubMed |
spelling | pubmed-97716942022-12-21 SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia Hoshii, Takayuki Perlee, Sarah Kikuchi, Sota Rahmutulla, Bahityar Fukuyo, Masaki Masuda, Takeshi Ohtsuki, Sumio Soga, Tomoyoshi Nabet, Behnam Kaneda, Atsushi Cell Rep Article Histone methyltransferase SETD1A is critical for acute myeloid leukemia (AML) cell survival, but the molecular mechanism driving SETD1A gene regulation remains elusive. To delineate the role of SETD1A, we utilize a protein degrader technology to induce rapid SETD1A degradation in AML cell lines. SETD1A degradation results in immediate downregulation of transcripts associated with DNA repair and heme biosynthesis pathways. CRISPR-based functional analyses and metabolomics reveal an essential role of SETD1A to maintain mitochondrial respiration in AML cells. These SETD1A targets are enriched in head-to-head (H2H) genes. SETD1A degradation disrupts a non-enzymatic SETD1A domain-dependent cyclin K function, increases the Ser5P RNA polymerase II (RNAPII) at the transcriptional start site (TSS), and induces the promoter-proximal pausing of RNAPII in a strand-specific manner. This study reveals a non-enzymatic role for SETD1A in transcriptional pause release and provides insight into the mechanism of RNAPII pausing and its function in cancer. 2022-11-29 /pmc/articles/PMC9771694/ /pubmed/36450243 http://dx.doi.org/10.1016/j.celrep.2022.111727 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ). |
spellingShingle | Article Hoshii, Takayuki Perlee, Sarah Kikuchi, Sota Rahmutulla, Bahityar Fukuyo, Masaki Masuda, Takeshi Ohtsuki, Sumio Soga, Tomoyoshi Nabet, Behnam Kaneda, Atsushi SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia |
title | SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia |
title_full | SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia |
title_fullStr | SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia |
title_full_unstemmed | SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia |
title_short | SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia |
title_sort | setd1a regulates transcriptional pause release of heme biosynthesis genes in leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9771694/ https://www.ncbi.nlm.nih.gov/pubmed/36450243 http://dx.doi.org/10.1016/j.celrep.2022.111727 |
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