Global Regulatory DNA Potentiation by SMARCA4 Propagates to Selective Gene Expression Programs via Domain-Level Remodeling
Summary: The human genome encodes millions of regulatory elements, of which only a small fraction are active within a given cell type. Little is known about the global impact of chromatin remodelers on regulatory DNA landscapes and how this translates to gene expression. We use precision genome engi...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-05-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472030629X |
| _version_ | 1828391698126864384 |
|---|---|
| author | John E. Lazar Sandra Stehling-Sun Vivek Nandakumar Hao Wang Daniel R. Chee Nicholas P. Howard Reyes Acosta Douglass Dunn Morgan Diegel Fidencio Neri Andres Castillo Sean Ibarrientos Kristen Lee Ninnia Lescano Ben Van Biber Jemma Nelson Jessica Halow Richard Sandstrom Daniel Bates Fyodor D. Urnov Alister P.W. Funnell John A. Stamatoyannopoulos |
| author_facet | John E. Lazar Sandra Stehling-Sun Vivek Nandakumar Hao Wang Daniel R. Chee Nicholas P. Howard Reyes Acosta Douglass Dunn Morgan Diegel Fidencio Neri Andres Castillo Sean Ibarrientos Kristen Lee Ninnia Lescano Ben Van Biber Jemma Nelson Jessica Halow Richard Sandstrom Daniel Bates Fyodor D. Urnov Alister P.W. Funnell John A. Stamatoyannopoulos |
| author_sort | John E. Lazar |
| collection | DOAJ |
| description | Summary: The human genome encodes millions of regulatory elements, of which only a small fraction are active within a given cell type. Little is known about the global impact of chromatin remodelers on regulatory DNA landscapes and how this translates to gene expression. We use precision genome engineering to reawaken homozygously inactivated SMARCA4, a central ATPase of the human SWI/SNF chromatin remodeling complex, in lung adenocarcinoma cells. Here, we combine DNase I hypersensitivity, histone modification, and transcriptional profiling to show that SMARCA4 dramatically increases both the number and magnitude of accessible chromatin sites genome-wide, chiefly by unmasking sites of low regulatory factor occupancy. By contrast, transcriptional changes are concentrated within well-demarcated remodeling domains wherein expression of specific genes is gated by both distal element activation and promoter chromatin configuration. Our results provide a perspective on how global chromatin remodeling activity is translated to gene expression via regulatory DNA. |
| first_indexed | 2024-12-10T07:06:43Z |
| format | Article |
| id | doaj.art-db020382c20c4e37938ec33f5f948e59 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T07:06:43Z |
| publishDate | 2020-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-db020382c20c4e37938ec33f5f948e592022-12-22T01:58:11ZengElsevierCell Reports2211-12472020-05-01318Global Regulatory DNA Potentiation by SMARCA4 Propagates to Selective Gene Expression Programs via Domain-Level RemodelingJohn E. Lazar0Sandra Stehling-Sun1Vivek Nandakumar2Hao Wang3Daniel R. Chee4Nicholas P. Howard5Reyes Acosta6Douglass Dunn7Morgan Diegel8Fidencio Neri9Andres Castillo10Sean Ibarrientos11Kristen Lee12Ninnia Lescano13Ben Van Biber14Jemma Nelson15Jessica Halow16Richard Sandstrom17Daniel Bates18Fyodor D. Urnov19Alister P.W. Funnell20John A. Stamatoyannopoulos21Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Altius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USADepartment of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Altius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USAAltius Institute for Biomedical Sciences, Seattle, WA 98121, USA; Corresponding authorDepartment of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA; Corresponding authorSummary: The human genome encodes millions of regulatory elements, of which only a small fraction are active within a given cell type. Little is known about the global impact of chromatin remodelers on regulatory DNA landscapes and how this translates to gene expression. We use precision genome engineering to reawaken homozygously inactivated SMARCA4, a central ATPase of the human SWI/SNF chromatin remodeling complex, in lung adenocarcinoma cells. Here, we combine DNase I hypersensitivity, histone modification, and transcriptional profiling to show that SMARCA4 dramatically increases both the number and magnitude of accessible chromatin sites genome-wide, chiefly by unmasking sites of low regulatory factor occupancy. By contrast, transcriptional changes are concentrated within well-demarcated remodeling domains wherein expression of specific genes is gated by both distal element activation and promoter chromatin configuration. Our results provide a perspective on how global chromatin remodeling activity is translated to gene expression via regulatory DNA.http://www.sciencedirect.com/science/article/pii/S221112472030629Xcancer epigeneticsSMARCA4BAF complexgene regulationchromatin accessibilitychromatin domains |
| spellingShingle | John E. Lazar Sandra Stehling-Sun Vivek Nandakumar Hao Wang Daniel R. Chee Nicholas P. Howard Reyes Acosta Douglass Dunn Morgan Diegel Fidencio Neri Andres Castillo Sean Ibarrientos Kristen Lee Ninnia Lescano Ben Van Biber Jemma Nelson Jessica Halow Richard Sandstrom Daniel Bates Fyodor D. Urnov Alister P.W. Funnell John A. Stamatoyannopoulos Global Regulatory DNA Potentiation by SMARCA4 Propagates to Selective Gene Expression Programs via Domain-Level Remodeling Cell Reports cancer epigenetics SMARCA4 BAF complex gene regulation chromatin accessibility chromatin domains |
| title | Global Regulatory DNA Potentiation by SMARCA4 Propagates to Selective Gene Expression Programs via Domain-Level Remodeling |
| title_full | Global Regulatory DNA Potentiation by SMARCA4 Propagates to Selective Gene Expression Programs via Domain-Level Remodeling |
| title_fullStr | Global Regulatory DNA Potentiation by SMARCA4 Propagates to Selective Gene Expression Programs via Domain-Level Remodeling |
| title_full_unstemmed | Global Regulatory DNA Potentiation by SMARCA4 Propagates to Selective Gene Expression Programs via Domain-Level Remodeling |
| title_short | Global Regulatory DNA Potentiation by SMARCA4 Propagates to Selective Gene Expression Programs via Domain-Level Remodeling |
| title_sort | global regulatory dna potentiation by smarca4 propagates to selective gene expression programs via domain level remodeling |
| topic | cancer epigenetics SMARCA4 BAF complex gene regulation chromatin accessibility chromatin domains |
| url | http://www.sciencedirect.com/science/article/pii/S221112472030629X |
| work_keys_str_mv | AT johnelazar globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT sandrastehlingsun globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT viveknandakumar globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT haowang globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT danielrchee globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT nicholasphoward globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT reyesacosta globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT douglassdunn globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT morgandiegel globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT fidencioneri globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT andrescastillo globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT seanibarrientos globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT kristenlee globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT ninnialescano globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT benvanbiber globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT jemmanelson globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT jessicahalow globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT richardsandstrom globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT danielbates globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT fyodordurnov globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT alisterpwfunnell globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling AT johnastamatoyannopoulos globalregulatorydnapotentiationbysmarca4propagatestoselectivegeneexpressionprogramsviadomainlevelremodeling |