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^*

^*Kontaktforfatter

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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.

Originalsprog	Engelsk
Tidsskrift	Nature Cell Biology
Vol/bind	24
Udgave nummer	8
Sider (fra-til)	1265–1277
ISSN	1465-7392
DOI	https://doi.org/10.1038/s41556-022-00971-3
Status	Udgivet - aug. 2022
Udgivet eksternt	Ja

Bibliografisk note

Funding Information:
We thank the members of the Tiwari lab for their cooperation and critical feedback throughout this study. We thank N. Hah from Salk Institute for Biological Studies for her feedback on fastGRO. The support from the Facilities of the Queen’s University Belfast is gratefully acknowledged. This study was supported by the Deutsche Forschungsgemeinschaft TI 799/1-3, Wilhelm Sander Stiftung 2012.009.1 and 2012.009.2 and ICURe to V.K.T. and the Marie Curie (PCIG12-GA-2012-334000) and ANR programme (CT-141033_ANR-16-CE12-0012-01) to R.F.L.

Dokumenter og links

10.1038/s41556-022-00971-3

SDU link

Tjek adgangen til materialet i Syddansk Universitetsbiblioteks søgemaskine

Citationsformater

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.",

keywords = "Alternative Splicing, Brain/metabolism, Breast Neoplasms/genetics, Cell Line, Tumor, Epigenome, Epithelial-Mesenchymal Transition/genetics, Female, Gene Expression Regulation, Neoplastic, Humans, Neoplasm 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.}",

note = "Funding Information: We thank the members of the Tiwari lab for their cooperation and critical feedback throughout this study. We thank N. Hah from Salk Institute for Biological Studies for her feedback on fastGRO. The support from the Facilities of the Queen{\textquoteright}s University Belfast is gratefully acknowledged. This study was supported by the Deutsche Forschungsgemeinschaft TI 799/1-3, Wilhelm Sander Stiftung 2012.009.1 and 2012.009.2 and ICURe to V.K.T. and the Marie Curie (PCIG12-GA-2012-334000) and ANR programme (CT-141033_ANR-16-CE12-0012-01) to R.F.L. ",

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month = aug,

doi = "10.1038/s41556-022-00971-3",

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T1 - A complex epigenome-splicing crosstalk governs epithelial-to-mesenchymal transition in metastasis and brain development

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.

N1 - Funding Information: We thank the members of the Tiwari lab for their cooperation and critical feedback throughout this study. We thank N. Hah from Salk Institute for Biological Studies for her feedback on fastGRO. The support from the Facilities of the Queen’s University Belfast is gratefully acknowledged. This study was supported by the Deutsche Forschungsgemeinschaft TI 799/1-3, Wilhelm Sander Stiftung 2012.009.1 and 2012.009.2 and ICURe to V.K.T. and the Marie Curie (PCIG12-GA-2012-334000) and ANR programme (CT-141033_ANR-16-CE12-0012-01) to R.F.L.

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N2 - 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.

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.

KW - Alternative Splicing

KW - Brain/metabolism

KW - Breast Neoplasms/genetics

KW - Cell Line, Tumor

KW - Epigenome

KW - Epithelial-Mesenchymal Transition/genetics

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Neoplasm Metastasis

U2 - 10.1038/s41556-022-00971-3

DO - 10.1038/s41556-022-00971-3

M3 - Journal article

C2 - 35941369

SN - 1465-7392

VL - 24

SP - 1265

EP - 1277

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 8

ER -

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

Abstract

Bibliografisk note

Dokumenter og links

SDU link

Fingeraftryk

Citationsformater