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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...

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Autores principales: Hoshii, Takayuki, Perlee, Sarah, Kikuchi, Sota, Rahmutulla, Bahityar, Fukuyo, Masaki, Masuda, Takeshi, Ohtsuki, Sumio, Soga, Tomoyoshi, Nabet, Behnam, Kaneda, Atsushi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
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.
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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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