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A complex epigenome-splicing crosstalk governs epithelial to mesenchymal transition in metastasis and brain development

ABSTRACT: Epithelial to Mesenchymal Transition (EMT) renders epithelial cells to acquire migratory characteristics during development and cancer metastasis. While epigenetic and splicing changes have been implicated in EMT, the mechanisms governing their crosstalk remain poorly understood. Here, we identify C2H2 zinc finger protein, ZNF827, a novel factor, is strongly induced during important EMT mediated processes including in brain development and breast cancer metastasis and is required for the molecular and phenotypic changes underlying EMT in these processes. Mechanistically, ZNF827 mediated these responses by orchestrating a large-scale remodeling of the splicing landscape by recruiting HDAC1 for epigenetic modulation of distinct genomic loci, thereby slowing RNA Pol II progression and altering the splicing of transcripts encoding key EMT regulators in cis. These findings reveal an unprecedented complexity between epigenetic landscape and splicing and identifies ZNF827 as a master regulator coupling these processes during EMT in brain development and breast cancer metastasis.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Mohammed Inayatullah

LAB HEAD: Dr. Vijay Tiwari

PROVIDER: PXD034511 | Pride | 2022-06-21

REPOSITORIES: Pride

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			Action	DRS
	20150113_QEP1_IMB_VT_0008_hs_IP_SIL_120.raw	Raw
	20150113_QEP1_IMB_VT_0009_hs_IP_SIL_120.raw	Raw
	proteinGroups_VT_0008-0009_filtered.dat	Other

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A complex epigenome-splicing crosstalk governs epithelial to mesenchymal transition in metastasis and brain development

Project description:Epithelial to Mesenchymal Transition (EMT) renders epithelial cells migratory properties. While epigenetic and splicing changes have been implicated in EMT, the mechanisms governing their crosstalk remain poorly understood. Here, we discovered a C2H2 zinc finger protein, ZNF827, is strongly induced during various contexts of EMT including in brain development and breast cancer metastasis and is required for the molecular and phenotypic changes underlying EMT in these processes. Mechanistically, ZNF827 mediated these responses by orchestrating a large-scale remodeling of the splicing landscape by recruiting HDAC1 for epigenetic modulation of distinct genomic loci, thereby slowing RNA Pol II progression and altering the splicing of genes encoding key EMT regulators in cis. Our findings reveal an unprecedented complexity of crosstalk between epigenetic landscape and splicing programme in governing EMT and identify ZNF827 as a master regulator coupling these processes during EMT in brain development and breast cancer metastasis.

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