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

Sanjeeb Kumar Sahu; Eneritz Agirre; Mohammed Inayatullah; Arun Mahesh; Neha Tiwari; Deborah P. Lavin; Aditi Singh; Susanne Strand; Mustafa Diken; Reini F. Luco; Juan Carlos Izpisua Belmonte; Vijay K. Tiwari

doi:10.1038/s41556-022-00971-3

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

Sanjeeb Kumar Sahu, Eneritz Agirre, Mohammed Inayatullah, Arun Mahesh, Neha Tiwari, Deborah P. Lavin, Aditi Singh, Susanne Strand, Mustafa Diken, Reini F. Luco, Juan Carlos Izpisua Belmonte, Vijay K. Tiwari^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

Abstract

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 that 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 remodelling of the splicing landscape by recruiting HDAC1 for epigenetic modulation of distinct genomic loci, thereby slowing RNA polymerase 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.

Original language	English
Pages (from-to)	1265-1277
Number of pages	13
Journal	Nature Cell Biology
Volume	24
Issue number	8
DOIs	https://doi.org/10.1038/s41556-022-00971-3
Publication status	Published - 08 Aug 2022

ASJC Scopus subject areas

Cell Biology

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Sahu, S. K., Agirre, E., Inayatullah, M., Mahesh, A., Tiwari, N., Lavin, D. P., Singh, A., Strand, S., Diken, M., Luco, R. F., Belmonte, J. C. I., & Tiwari, V. K. (2022). A complex epigenome-splicing crosstalk governs epithelial-to-mesenchymal transition in metastasis and brain development. Nature Cell Biology, 24(8), 1265-1277. https://doi.org/10.1038/s41556-022-00971-3

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

abstract = "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 that 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 remodelling of the splicing landscape by recruiting HDAC1 for epigenetic modulation of distinct genomic loci, thereby slowing RNA polymerase 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.",

author = "Sahu, {Sanjeeb Kumar} and Eneritz Agirre and Mohammed Inayatullah and Arun Mahesh and Neha Tiwari and Lavin, {Deborah P.} and Aditi Singh and Susanne Strand and Mustafa Diken and Luco, {Reini F.} and Belmonte, {Juan Carlos Izpisua} and Tiwari, {Vijay K.}",

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AU - Sahu, Sanjeeb Kumar

AU - Agirre, Eneritz

AU - Inayatullah, Mohammed

AU - Mahesh, Arun

AU - Tiwari, Neha

AU - Lavin, Deborah P.

AU - Singh, Aditi

AU - Strand, Susanne

AU - Diken, Mustafa

AU - Luco, Reini F.

AU - Belmonte, Juan Carlos Izpisua

AU - Tiwari, Vijay K.

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AB - 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 that 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 remodelling of the splicing landscape by recruiting HDAC1 for epigenetic modulation of distinct genomic loci, thereby slowing RNA polymerase 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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JF - Nature Cell Biology

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ER -

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

Abstract

ASJC Scopus subject areas

UN SDGs

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