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The BOD1L subunit of the SETD1A complex sustains the expression of DNA damage repair genes despite restraining H3K4 trimethylation [single_end_RNAseq]

ABSTRACT: Background SETD1A is the histone 3 lysine 4 (H3K4) methyltransferase central to the mammalian version of the highly conserved eight subunit Set1 complex (Set1C) that apparently conveys H3K4 trimethylation (H3K4me3) onto all active Pol II promoters. Accordingly, the Setd1a mouse knock-out dies in early embryogenesis at the epiblast stage and mouse embryonic stem cells (ESCs) die when SETD1A is removed. Results We report that ESC death is accompanied by loss of expression of DNA repair genes and accumulating DNA damage. BOD1L and BOD1 are homologs of the yeast Set1C subunit, Shg1, and subunits of the mammalian SETD1A and B complexes. We show that the Shg1 homology region binds to a highly conserved central a-helix in SETD1A and B. Like mutagenesis of Shg1 in yeast, conditional mutagenesis of Bod1l in ESCs promoted increased H3K4 di- and tri-methylation but also, like loss of SETD1A, loss of expression of DNA repair genes, increased DNA damage and cell death. Conclusions In contrast to similar losses of DNA repair gene expression, the converse changes in H3K4 methylation after loss of SETD1A or BOD1L implies that H3K4 methylation is not essential for expression of the DNA repair network genes. Because BOD1L becomes highly phosphorylated after DNA damage and acts to protect damaged replication forks, the SETD1A complex, and BOD1L in particular, are key nodes for the DNA damage repair network.

ORGANISM(S): Mus musculus

PROVIDER: GSE319677 | GEO | 2026/02/18

REPOSITORIES: GEO

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The BOD1L subunit of the SETD1A complex sustains the expression of DNA damage repair genes despite restraining H3K4 trimethylation [paired_end_RNAseq]

Project description:Background SETD1A is the histone 3 lysine 4 (H3K4) methyltransferase central to the mammalian version of the highly conserved eight subunit Set1 complex (Set1C) that apparently conveys H3K4 trimethylation (H3K4me3) onto all active Pol II promoters. Accordingly, the Setd1a mouse knock-out dies in early embryogenesis at the epiblast stage and mouse embryonic stem cells (ESCs) die when SETD1A is removed. Results We report that ESC death is accompanied by loss of expression of DNA repair genes and accumulating DNA damage. BOD1L and BOD1 are homologs of the yeast Set1C subunit, Shg1, and subunits of the mammalian SETD1A and B complexes. We show that the Shg1 homology region binds to a highly conserved central a-helix in SETD1A and B. Like mutagenesis of Shg1 in yeast, conditional mutagenesis of Bod1l in ESCs promoted increased H3K4 di- and tri-methylation but also, like loss of SETD1A, loss of expression of DNA repair genes, increased DNA damage and cell death. Conclusions In contrast to similar losses of DNA repair gene expression, the converse changes in H3K4 methylation after loss of SETD1A or BOD1L implies that H3K4 methylation is not essential for expression of the DNA repair network genes. Because BOD1L becomes highly phosphorylated after DNA damage and acts to protect damaged replication forks, the SETD1A complex, and BOD1L in particular, are key nodes for the DNA damage repair network.

2026-02-18 | GSE319676 | GEO

BOD1L mediates chromatin binding and non-canonical function of H3K4 methyltransferase SETD1A (RNA-seq)

Project description:The H3K4 methyltransferase SETD1A plays an essential role in both development and cancer. However, essential components involved in SETD1A chromatin binding remain unclear. Here, we discovered that BOD1L exhibits the highest correlated co-dependency with SETD1A in human cancer cell lines. BOD1L knockout reduces leukemia cells in vitro and in vivo, and mimics the transcriptional profiles observed in SETD1A knockout cells. The loss of BOD1L immediately reduced SETD1A distribution at transcriptional start sites (TSS) and induces transcriptional elongation defect along with the increasing of RNA polymerase II at TSS, but did not cause the reduction of H3K4me3. The Shg1 domain of BOD1L has a DNA binding ability, and recruit SETD1A to chromatin through the association with SETD1A FLOS domain. In addition, the BOD1L-SETD1A complex associates with transcriptional regulators, including E2Fs. These results reveal that BOD1L mediates chromatin and SETD1A, and regulates the non-canonical function of SETD1A in transcription.

2024-06-25 | GSE258789 | GEO

BOD1L mediates chromatin binding and non-canonical function of H3K4 methyltransferase SETD1A (ChIP-seq)

2024-06-25 | GSE258788 | GEO

IPs of SETD1A COMPASS-HUMAN LC-MSMS

Project description:Mapping physical interactions of SETD1A COMPOASS in HEK293T cells using endogenous immunoprecipitation followed by label-free quantitative proteomics. We found a novel protein interacts with SETD1A, which is RAD18 (DNA damage repair protein).

2019-06-13 | PXD012549 | Pride

A non-catalytic function of SETD1A regulates Cyclin K and the DNA damage response [RNA-seq]

Project description:MLL/SET methyltransferases catalyze methylation of histone 3 lysine 4 and play critical roles in development and cancer. We assessed MLL/SET proteins and found that SETD1A is required for survival of acute myeloid leukemia (AML) cells. Mutagenesis studies and CRISPR-Cas9 domain screening, showed the enzymatic SET domain is not necessary for AML cell survival but that a newly identified region, termed the FLOS (Functional Location on SETD1A) domain, is indispensable. FLOS disruption suppresses DNA damage response genes and induces p53-dependent apoptosis. The FLOS domain acts as a Cyclin K-binding site that is required for chromosomal recruitment of Cyclin K, and for DNA repair-associated gene expression in S phase. These data identify a connection between the chromatin regulator SETD1A and the DNA damage response that is independent of histone methylation, and suggests that targeting SETD1A and Cyclin K complexes may represent a therapeutic opportunity for AML and potentially other cancers.

2018-02-01 | GSE108614 | GEO

SETD1A Regulates Psychiatric Gene Networks Involved in Genomic Stability and Synaptic Function in Rare and Sporadic Schizophrenia [bulk RNA-seq]

Project description:Rare loss-of-function (LoF) mutations in SETD1A are associated with schizophrenia (SCZ). However, how SETD1A haploinsufficiency leads to SCZ-associated phenotypes and its relevance to patients without these rare mutations is unknown. Here, we identify SETD1A bound loci and regulated genes in human prenatal cortex and isogenic pluripotent stem cell-derived neuronal models engineered with SETD1A LoF variants, including the most common patient mutation. SETD1A preferentially binds the promoters of SCZ and Bipolar risk loci that regulate chromatin remodeling, DNA repair, and synaptic function. Additionally, SETD1A binds to DNA damage prone sites in neural progenitor cells and postmitotic neurons. SETD1A haploinsufficiency causes accelerated neurogenesis, reduced neuronal complexity, and DNA damage accumulation in postmitotic neurons that is rescued by inhibiting the H3K4me2/3 demethylase KDM5. In postmortem SCZ cortical tissue, individuals who lack SETD1A mutations exhibit reduced SETD1A expression, associated with downregulation of SETD1A-regulated genes, implicating SETD1A-H3K4me dysfunction in sporadic SCZ cases. Therefore, restoring the SETD1A-H3K4me epigenetic imbalance may benefit individuals with SETD1A haploinsufficiency as well as a broader psychiatric population without SETD1A mutations.

2025-09-15 | GSE293155 | GEO

SETD1A Regulates Psychiatric Gene Networks Involved in Genomic Stability and Synaptic Function in Rare and Sporadic Schizophrenia [CUT&Tag]

2025-09-15 | GSE293154 | GEO

SETD1A Regulates Psychiatric Gene Networks Involved in Genomic Stability and Synaptic Function in Rare and Sporadic Schizophrenia

2025-09-15 | GSE293325 | GEO

SETD1A is required for intestinal homeostasis and prevention of DNA damage

Project description:The impact of SETD1A on the small intestine was evaluated in sorted intestinal stem, transit amplifying (TA) and Paneth cells from Setd1aFC/+; Lgr5-eGFP-CreERT2/+ (control) and Setd1aFC/FC; Lgr5-eGFP-CreERT2/+ (knockout) mice, 4 days after tamoxifen-induced mutagenesis. Using 100-base-pair reads, over 35 million reads per sample with comparable unique mapped reads were obtained. To analyze differentially expressed genes, we applied DESeq2 analysis to the RNA-seq dataset. Analysis by DAVID and GSEA at a false discovery rate (FDR) of 5% was conducted.The stem and TA cell transcriptome revealed that Setd1a knockout cells exhibited a decreased expression of several DNA damage repair genes.

2025-12-07 | GSE220632 | GEO

N-terminal acetylation of the Set1-COMPASS fine-tunes H3K4 methylation patterns (ChIPseq for ard1 deletion strain)

Project description:H3K4 methylation is a conserved histone modification crucial for gene regulation, yet the post-translational modifications of the Set1-COMPASS complex remain largely unexplored. This study elucidates the significance of N-terminal acetylation in modulating H3K4 methylation patterns. Firstly, loss of NatA complex resulted in a significant decrease in H3K4me3 levels and a shift of H3K4me2 from 5' transcribed regions to promoters. Importantly, NatA physically interacted with the Set1-COMPASS complex and facilitated N-terminal acetylation of the Shg1 subunit. Surprisingly, deletion of SHG1 or mutation of the acetylation site (A2P) in Shg1 led to reduced H3K4 methylation in cells lacking Spp1. Additionally, NatB complex also contributed to H3K4 methylation regulation, potentially through N-terminal acetylation of Swd1. These findings highlight the novel role of N-terminal acetylation in fine-tuning the function of the Set1-COMPASS complex and shaping H3K4 methylation patterns. This study sheds light on the intricate regulation of H3K4 methylation and emphasizes the significance of N-terminal acetylation as a regulatory mechanism in this process.

2024-05-31 | GSE238069 | GEO

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