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

doi:10.1016/j.celrep.2022.111727

Cited by 6 publications

(3 citation statements)

References 55 publications

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“…These include nodes with characterized or inferred roles in thermal regulation, such as the acetyltransferases Crebbp/CBP, EP300/p300, and Kat2a/Gcn5; deacetylases such as members of the HDAC and sirtuin families; methyltransferase members of the KMT2 family as well as Mettl3; and the KDM family demethylases (Artsi et al, 2019;Chen et al, 2021;Dovey et al, 2010;Emmett et al, 2017;Mutlu and Puigserver, 2021;Namwanje et al, 2019;Sambeat et al, 2017;Wang et al, 2020;Yan et al, 2021;Yao et al, 2017). We observe particularly strong footprints among cold challenge-induced genes for Setd1a, which has only recently been implicated in thermogenesis (Hoshii et al, 2022). In addition to these nodes, our analysis hints at roles for a number of nodes with no previously resolved role in the response to cold challenge, such as Cdyl, Kat5/TIP60, Kat8, Ash2l, Ehmt2 and Setdb1.…”

Section: Regulatory Network Analysis Resolves Epigenetic Writer Footp...mentioning

confidence: 86%

Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress

Taylor,

Steinthal,

Dias

et al. 2023

Preprint

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Regulation of the thermogenic response by brown adipose tissue (BAT) is an important component of energy homeostasis with implications for the treatment of obesity and diabetes. Motivated to understand how BAT function is regulated epigenetically, we reanalyzed publicly available RNA-seq data and uncovered many nodes representing epigenetic modifiers that are altered in BAT in response to chronic thermogenic activation. Thus, we hypothesized that chronic thermogenic activation broadly alters epigenetic modifications of DNA and histones in BAT. To test our hypothesis, wildtype male C57BL/6J mice were housed under chronic conditions of thermoneutral temperature (TN, 28.8°C), mild cold/room temperature (RT, 22°C), or severe cold (SC, 8°C). BAT and reference tissue liver were subsequently dissected from each mouse. Reduced representation bisulfite sequencing (RRBS) reveals decreased methylation of promoters and intragenic regions in BAT genomic DNA in response to varying degrees of chronic cold exposure. Integration of our RRBS and the RNA-Seq dataset suggests a role for epigenetic modification of DNA in gene regulation in response to cold. To analyze histone modifications in BAT, we develop a robust method for the isolation of histones and report the first quantitation of histone H3.2 and H4 proteoforms. We initially observe that BAT and liver exhibit different histone proteoforms. Next, we report housing temperature-dependent changes in histone proteoforms in BAT. We observe differences in bivalent proteoforms such as H3{K9me2,K23ac,K36me1}, H3{K9me3,K23ac,K36me1} and H4<K8acK16acK20me3>. Taken together, our results provide novel findings supporting global epigenetic modification in murine BAT in response to varying degrees of chronic cold stimuli and establish a methodology to quantitatively study histones in BAT, allowing for direct comparisons to decipher mechanistic changes during the thermogenic response.

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Section: Regulatory Network Analysis Resolves Epigenetic Writer Footp...mentioning

confidence: 86%

Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress

Taylor,

Steinthal,

Dias

et al. 2023

Preprint

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“…SETD1A-mediated pause release is achieved by interacting with cyclin K, which recruits CDK9 (a component of P-TEFb) to the promoter region. ( 65 ). Therefore, it is possible that a ZFX-COMPASS interaction also contributes to release of paused Pol2 independent of effects on levels of H3K4me3.…”

Section: Discussionmentioning

confidence: 99%

Reduction of ZFX levels decreases histone H4 acetylation and increases Pol2 pausing at target promoters

Hsu,

Hutchison,

Liu

et al. 2024

Nucleic Acids Research

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The ZFX transcriptional activator binds to CpG island promoters, with a major peak at ∼200–250 bp downstream from transcription start sites. Because ZFX binds within the transcribed region, we investigated whether it regulates transcriptional elongation. We used GRO-seq to show that loss or reduction of ZFX increased Pol2 pausing at ZFX-regulated promoters. To further investigate the mechanisms by which ZFX regulates transcription, we determined regions of the protein needed for transactivation and for recruitment to the chromatin. Interestingly, although ZFX has 13 grouped zinc fingers, deletion of the first 11 fingers produces a protein that can still bind to chromatin and activate transcription. We next used TurboID-MS to detect ZFX-interacting proteins, identifying ZNF593, as well as proteins that interact with the N-terminal transactivation domain (which included histone modifying proteins), and proteins that interact with ZFX when it is bound to the chromatin (which included TAFs and other histone modifying proteins). Our studies support a model in which ZFX enhances elongation at target promoters by recruiting H4 acetylation complexes and reducing pausing.

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“…The previously established MOLM‐13 leukemia cells expressing HA‐tagged SETD1A (Hoshii et al , 2022) were fixed with 2 mM DSG for 30 min followed by 1% formaldehyde for 10 min and treated with 0.125 M Glycine for 5 min. Fixed cells were washed twice with cold PBS.…”

Section: Methodsmentioning

confidence: 99%

SETD1A function in leukemia is mediated through interaction with mitotic regulators BuGZ/BUB3

et al. 2023

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The H3K4 methyltransferase SETD1A plays a crucial role in leukemia cell survival through its noncatalytic FLOS domain‐mediated recruitment of cyclin K and regulation of DNA damage response genes. In this study, we identify a functional nuclear localization signal in and interaction partners of the FLOS domain. Our screen for FLOS domain‐binding partners reveals that the SETD1A FLOS domain binds mitosis‐associated proteins BuGZ/BUB3. Inhibition of both cyclin K and BuGZ/BUB3‐binding motifs in SETD1A shows synergistic antileukemic effects. BuGZ/BUB3 localize to SETD1A‐bound promoter‐TSS regions and SETD1A‐negative H3K4me1‐positive enhancer regions adjacent to SETD1A target genes. The GLEBS motif and intrinsically disordered region of BuGZ are required for both SETD1A‐binding and leukemia cell proliferation. Cell‐cycle‐specific SETD1A restoration assays indicate that SETD1A expression at the G1/S phase of the cell cycle promotes both the expression of DNA damage response genes and cell cycle progression in leukemia cells.

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SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia

Cited by 6 publications

References 55 publications

Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress

Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress

Reduction of ZFX levels decreases histone H4 acetylation and increases Pol2 pausing at target promoters

SETD1A function in leukemia is mediated through interaction with mitotic regulators BuGZ/BUB3

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