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Nuclear-localized HKDC1 promotes hepatocellular carcinoma through phosphorylating RBBP5 to activate H3K4me3 [RNA-Seq]

ABSTRACT: Histone methyltransferases KMT2A (also known as mixed lineage leukemia 1, MLL1) can convert H3K4me1 to H3K4me2 with limited activity. However, it fully trimethylates H3K4 when associated with core subunits, including WDR5, RBBP5, ASH2L, and DPY30. We demonstrated that HKDC1 binds and phosphorylates RBBP5, promoting the assembly of MLL1 complex and the activating H3K4me3. Consequently, HKDC1 transcriptionally activates gene expression. We used CUT&Tag to study H3K4me3 levels of the promoter regions regulated by HKDC1 and RBBP5. Here, we also performed RNA-seq assay in PLC cells with HKDC1 or RBBP5 knocked down to study the role of HKDC1 and RBBP5 in regulating gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275644 | GEO | 2025/01/12

REPOSITORIES: GEO

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Nuclear-localized HKDC1 promotes hepatocellular carcinoma through phosphorylating RBBP5 to activate H3K4me3

Project description:Histone methyltransferases KMT2A (also known as mixed lineage leukemia 1, MLL1) can convert H3K4me1 to H3K4me2 with limited activity. However, it fully trimethylates H3K4 when associated with core subunits, including WDR5, RBBP5, ASH2L, and DPY30. We demonstrated that HKDC1 binds and phosphorylates RBBP5, promoting the assembly of MLL1 complex and the activating H3K4me3. Here, we used CUT&Tag to study H3K4me3 levels of the promoter regions regulated by HKDC1 and RBBP5. We knocked down HKDC1 or RBBP5 in PLC cells and performed CUT&Tag assay.

2025-01-12 | GSE275531 | GEO

Nuclear-localized HKDC1 promotes hepatocellular carcinoma through phosphorylating RBBP5 to upregulate H3K4me3

Project description:Metabolic enzymes play significant roles in the pathogenesis of various cancers through both canonical and noncanonical functions. Hexokinase domain-containing protein 1 (HKDC1) functions beyond glucose metabolism, but its underlying mechanisms in tumorigenesis are not fully understood. Here, we demonstrate that nuclear-localized HKDC1 acts as a protein kinase to promote hepatocellular carcinoma (HCC) cell proliferation. Mechanistically, HKDC1 phosphorylates RB binding protein 5 (RBBP5) at Ser497, which is crucial for MLL1 complex assembly and subsequent H3K4me3 modification. This leads to the transcriptional activation of mitosis-related genes, thereby driving cell cycle progression and proliferation. Notably, targeting HKDC1’s protein kinase activity, but not its hexokinase activity, blocks RBBP5 phosphorylation and suppresses tumor growth. Clinical analysis further reveals that RBBP5 phosphorylation positively correlates with HKDC1 levels and poor HCC prognosis. These findings highlight the protein kinase function of HKDC1 in the activation of H3K4me3, gene expression, and HCC progression.

2025-01-07 | PXD059464 | Pride

Multistate structures of the MLL1-WRAD complex bound to H2B-ubiquitinated nucleosome

Project description:The human Mixed Lineage Leukemia-1 (MLL1) complex orchestrates methylation of histone H3K4 to promote transcription and is the target of chromosomal translocations in a variety of leukemias. The MLL1 core complex comprises the MLL1 methyltransferase and the WRAD complex, which contains WDR5, RbBp5, Ash2L, and DPY-30. Recent studies have shed light on the structure and organization of the human MLL1-WRAD complex bound to nucleosomes but were not able to resolve portions of the Ash2L subunit or DPY30. We used an integrated approach combining cryo-electron microscopy and mass spectrometry-cross linking to obtain models of the MLL1-WRAD complex bound to nucleosomes containing monoubiquitinated histone H2B, which is reported to stimulate H3K4 methylation. We constructed a model containing the Ash2L intrinsically disordered region (IDR), SPRY insertion region, and Sdc1-DPY30 interacting region (SDI-motif), as well as the DPY30 dimer, which were not resolved in previous structures. In addition to the model of the active state, we resolved three additional states of MLL1-WRAD lacking one or more subunits that may reflect different steps in the assembly of MLL1-WRAD. Our results provide a more complete picture of MLL1-WRAD and how it assembles on nucleosomes to form an active methyltransferase complex.

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Genome-wide distribution of Ash2L and H3K4me3 in mouse embryonic stem cell line E14

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Induction of senescence upon loss of the Ash2l subunit of histone H3K4 methyltransferase complexes (RNA-Seq)

Project description:Post-translational modifications of core histones participate in controlling the expression of genes. Methylation of lysine 4 of histone H3 (H3K4) is associated with open chromatin and gene transcription. This histone mark is catalyzed by type 2 lysine methyltransferase (KMT2) complexes. In mammals, these consist of one of 6 different KMT2 enzymes, each associated with 4 core subunits, WDR5, RBBP5, ASH2L and DPY30, which are necessary for catalytic activity. The knockout of Ash2l is embryonically lethal in mice as well as in adult animals when hepatocytes or hematopoietic cells are targeted. To expand on the mechanistic understanding of Ash2l, we have used mouse embryo fibroblasts (MEFs). The knockout of Ash2l resulted in the downregulation of H3K4me3 at a large number of promoters, preferentially those associated with CpG islands, accompanied with broad repression of gene expression. The consequence in MEFs was induction of senescence concomitant with a set of down-regulated signature genes. Thus, although the loss of Ash2l in MEFs has broad and complex consequences on the transcriptional program, the biological consequences were distinct, culminating in senescence.

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Induction of senescence upon loss of the Ash2l subunit of histone H3K4 methyltransferase complexes (ChIP-Seq)

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Loss of the Ash2l subunit of histone H3K4 methyltransferase complexes promotes chromatin compaction at promoters [ATAC-seq]

Project description:Cell fate decisions are closely associated with changes in gene expression programs. A large number of post-translational modifications of core histones contribute to controlling the expression of genes. A modification that is closely correlated with open chromatin and gene transcription is methylation of lysine 4 of histone H3 (H3K4). It is catalyzed by methyltransferases of the KMT2 family, which require interaction with 4 core subunits, WDR5, RBBP5, ASH2L and DPY30, for catalytic activity. Ash2l is required for organismal development and for tissue homeostasis in the mouse. In mouse embryo fibroblasts (MEFs), the loss of Ash2l results in downregulated gene expression, which provokes a senescence phenotype. We now find that both H3K4 mono- and tri-methylation (H3K4me1 and me3, respectively) are deregulated. H3K4me3 is lost while H3K4me1 is increased at promoters upon knockout of Ash2l. In particular, loss of H3K4me3 at promoters correlates with downregulation of gene expression, which is particularly obvious at CpG island promoters. Ash2l loss results in an increase of histone H3 loading at promoters, paralleled by enhanced chromatin compaction. This is accompanied by an increase of repressing and a decrease of activating histone marks. One of the sequence-specific transcription factors with altered binding upon depletion of Ash2l is CTCF. It is lost from some promoter-associated sites, but gained binding in other regions of the genome. This suggests that in addition to the well-known effects on H3K4 methylation upon depleting KMT2 complex components, Ash2l loss affects chromatin compaction. Whether the decrease of H3K4me3 promotes chromatin compaction at promoters or whether these are independent consequences of Ash2l loss remains to be determined. We suggest that both contribute mechanistically to gene repression and thus to the observed cellular effects.

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