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Alternative Splicing of HDAC7 Regulates its Interaction with 14-3-3 Proteins to Alter Histone Marks and Target Gene Expression

ABSTRACT: Epigenetics and Alternative Splicing are both critical mechanisms guiding gene expression. Several studies have demonstrated that epigenetic marks can influence alternative splicing decisions, but less is known about how alternative splicing may impact epigenetics. Here, we demonstrate that several genes encoding histone modifying enzymes are alternatively spliced downstream of T cell activation signaling pathways, including HDAC7, a gene previously implicated in controlling gene expression programs and differentiation in T cells. Using CRISPR-Cas9 gene editing and cDNA expression, we show that differential inclusion of HDAC7 exon 9 controls the interaction of HDAC7 with protein chaperones with resulting impact on histone modifications and gene expression. Notably, the long isoform, which is favored upon JNK signaling, promotes expression of several critical T cell surface proteins including CD3, CD28, CD69. Thus, we demonstrate that alternative splicing of HDAC7 has a global impact on epigenetics and gene expression, and may contribute to T cell regulation.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Jurkat Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Laura Agosto

LAB HEAD: Kristen W. Lynch

PROVIDER: PXD036471 | Pride | 2023-02-18

REPOSITORIES: Pride

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			Action	DRS
	220322_stim_WT_1.raw	Raw
	220322_stim_WT_2_rerun.raw	Raw
	220322_stim_WT_3.raw	Raw
	220322_stim_dE9_1_rerun.raw	Raw
	220322_stim_dE9_2.raw	Raw

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Alternative Splicing of HDAC7 Regulates its Interaction with 14-3-3 Proteins to Alter Histone Marks and Target Gene Expression

Project description:Epigenetics and Alternative Splicing are both critical mechanisms guiding gene expression. Several studies have demonstrated that epigenetic marks can influence alternative splicing decisions, but less is known about how alternative splicing may impact epigenetics. Here, we demonstrate that several genes encoding histone modifying enzymes are alternatively spliced downstream of T cell activation signaling pathways, including HDAC7, a gene previously implicated in controlling gene expression programs and differentiation in T cells. Using CRISPR-Cas9 gene editing and cDNA expression, we show that differential inclusion of HDAC7 exon 9 controls the interaction of HDAC7 with protein chaperones with resulting impact on histone modifications and gene expression. Notably, the long isoform, which is favored upon JNK signaling, promotes expression of several critical T cell surface proteins including CD3, CD28, CD69. Thus, we demonstrate that alternative splicing of HDAC7 has a global impact on epigenetics and gene expression, and may contribute to T cell regulation.

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Global regulation of alternative splicing by adenosine deaminase acting on RNA (ADAR) [RNA-seq]

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