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Article ; Online: Dissection of a CTCF topological boundary uncovers principles of enhancer-oncogene regulation.

Kim, Kyung Lock / Rahme, Gilbert J / Goel, Viraat Y / El Farran, Chadi A / Hansen, Anders S / Bernstein, Bradley E

2024 Volume 84, Issue 7, Page(s) 1365–1376.e7

Abstract: Enhancer-gene communication is dependent on topologically associating domains (TADs) and boundaries enforced by the CCCTC-binding factor (CTCF) insulator, but the underlying structures and mechanisms remain controversial. Here, we investigate a boundary ... ...

Abstract	Enhancer-gene communication is dependent on topologically associating domains (TADs) and boundaries enforced by the CCCTC-binding factor (CTCF) insulator, but the underlying structures and mechanisms remain controversial. Here, we investigate a boundary that typically insulates fibroblast growth factor (FGF) oncogenes but is disrupted by DNA hypermethylation in gastrointestinal stromal tumors (GISTs). The boundary contains an array of CTCF sites that enforce adjacent TADs, one containing FGF genes and the other containing ANO1 and its putative enhancers, which are specifically active in GIST and its likely cell of origin. We show that coordinate disruption of four CTCF motifs in the boundary fuses the adjacent TADs, allows the ANO1 enhancer to contact FGF3, and causes its robust induction. High-resolution micro-C maps reveal specific contact between transcription initiation sites in the ANO1 enhancer and FGF3 promoter that quantitatively scales with FGF3 induction such that modest changes in contact frequency result in strong changes in expression, consistent with a causal relationship.
MeSH term(s)	CCCTC-Binding Factor/genetics ; CCCTC-Binding Factor/metabolism ; Chromatin/genetics ; Enhancer Elements, Genetic ; Oncogenes ; DNA/chemistry
Chemical Substances	CCCTC-Binding Factor ; Chromatin ; DNA (9007-49-2)
Language	English
Publishing date	2024-03-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2024.02.007
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Article ; Online: Modeling epigenetic lesions that cause gliomas.

Rahme, Gilbert J / Javed, Nauman M / Puorro, Kaitlyn L / Xin, Shouhui / Hovestadt, Volker / Johnstone, Sarah E / Bernstein, Bradley E

Cell

2023 Volume 186, Issue 17, Page(s) 3674–3685.e14

Abstract: Epigenetic lesions that disrupt regulatory elements represent potential cancer drivers. However, we lack experimental models for validating their tumorigenic impact. Here, we model aberrations arising in isocitrate dehydrogenase-mutant gliomas, which ... ...

Abstract	Epigenetic lesions that disrupt regulatory elements represent potential cancer drivers. However, we lack experimental models for validating their tumorigenic impact. Here, we model aberrations arising in isocitrate dehydrogenase-mutant gliomas, which exhibit DNA hypermethylation. We focus on a CTCF insulator near the PDGFRA oncogene that is recurrently disrupted by methylation in these tumors. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce Pdgfra, thereby increasing proliferation. We show that a second lesion, methylation-dependent silencing of the Cdkn2a tumor suppressor, cooperates with insulator loss in OPCs. Coordinate inactivation of the Pdgfra insulator and Cdkn2a drives gliomagenesis in vivo. Despite locus synteny, the insulator is CpG-rich only in humans, a feature that may confer human glioma risk but complicates mouse modeling. Our study demonstrates the capacity of recurrent epigenetic lesions to drive OPC proliferation in vitro and gliomagenesis in vivo.
MeSH term(s)	Animals ; Humans ; Mice ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; DNA Methylation ; Epigenesis, Genetic ; Glioma/genetics ; Glioma/pathology ; Isocitrate Dehydrogenase/genetics ; Mutation ; Oncogenes ; Receptor, Platelet-Derived Growth Factor alpha/genetics
Chemical Substances	Isocitrate Dehydrogenase (EC 1.1.1.41) ; Receptor, Platelet-Derived Growth Factor alpha (EC 2.7.10.1) ; Cdkn2a protein, mouse
Language	English
Publishing date	2023-07-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2023.06.022
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Zs.A 1167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 58: Show issues

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Article ; Online: Epigenetic profiling reveals key genes and cis-regulatory networks specific to human parathyroids.

Jung, Youngsook Lucy / Zhao, Wenping / Li, Ian / Jain, Dhawal / Epstein, Charles B / Bernstein, Bradley E / Parangi, Sareh / Sherwood, Richard / Robinson-Cohen, Cassianne / Hsu, Yi-Hsiang / Park, Peter J / Mannstadt, Michael

Nature communications

2024 Volume 15, Issue 1, Page(s) 2106

Abstract: In all terrestrial vertebrates, the parathyroid glands are critical regulators of calcium homeostasis and the sole source of parathyroid hormone (PTH). Hyperparathyroidism and hypoparathyroidism are clinically important disorders affecting multiple ... ...

Abstract	In all terrestrial vertebrates, the parathyroid glands are critical regulators of calcium homeostasis and the sole source of parathyroid hormone (PTH). Hyperparathyroidism and hypoparathyroidism are clinically important disorders affecting multiple organs. However, our knowledge regarding regulatory mechanisms governing the parathyroids has remained limited. Here, we present the comprehensive maps of the chromatin landscape of the human parathyroid glands, identifying active regulatory elements and chromatin interactions. These data allow us to define regulatory circuits and previously unidentified genes that play crucial roles in parathyroid biology. We experimentally validate candidate parathyroid-specific enhancers and demonstrate their integration with GWAS SNPs for parathyroid-related diseases and traits. For instance, we observe reduced activity of a parathyroid-specific enhancer of the Calcium Sensing Receptor gene, which contains a risk allele associated with higher PTH levels compared to the wildtype allele. Our datasets provide a valuable resource for unraveling the mechanisms governing parathyroid gland regulation in health and disease.
MeSH term(s)	Animals ; Humans ; Calcium/metabolism ; Parathyroid Glands/metabolism ; Parathyroid Hormone/genetics ; Parathyroid Hormone/metabolism ; Chromatin/genetics ; Epigenesis, Genetic
Chemical Substances	Calcium (SY7Q814VUP) ; Parathyroid Hormone ; Chromatin
Language	English
Publishing date	2024-03-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-46181-3
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Article ; Online: Epigenome editing strategies for the functional annotation of CTCF insulators.

Tarjan, Daniel R / Flavahan, William A / Bernstein, Bradley E

Nature communications

2019 Volume 10, Issue 1, Page(s) 4258

Abstract: The human genome is folded into regulatory units termed 'topologically-associated domains' (TADs). Genome-wide studies support a global role for the insulator protein CTCF in mediating chromosomal looping and the topological constraint of TAD boundaries. ...

Abstract	The human genome is folded into regulatory units termed 'topologically-associated domains' (TADs). Genome-wide studies support a global role for the insulator protein CTCF in mediating chromosomal looping and the topological constraint of TAD boundaries. However, the impact of individual insulators on enhancer-gene interactions and transcription remains poorly understood. Here, we investigate epigenome editing strategies for perturbing individual CTCF insulators and evaluating consequent effects on genome topology and transcription. We show that fusions of catalytically-inactive Cas9 (dCas9) to transcriptional repressors (dCas9-KRAB) and DNA methyltransferases (dCas9-DNMT3A, dCas9-DNMT3A3L) can selectively displace CTCF from specific insulators, but only when precisely targeted to the cognate motif. We further demonstrate that stable, partially-heritable insulator disruption can be achieved through combinatorial hit-and-run epigenome editing. Finally, we apply these strategies to simulate an insulator loss mechanism implicated in brain tumorigenesis. Our study provides strategies for stably modifying genome organization and gene activity without altering the underlying DNA sequence.
MeSH term(s)	Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; CCCTC-Binding Factor/genetics ; CRISPR-Associated Protein 9/genetics ; CRISPR-Cas Systems/genetics ; Carcinogenesis/genetics ; Carcinogenesis/pathology ; Cell Line ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA Methylation ; Epigenesis, Genetic/genetics ; Gene Editing/methods ; Genome, Human/genetics ; HEK293 Cells ; Humans ; Promoter Regions, Genetic/genetics ; Recombinant Fusion Proteins/genetics ; Repressor Proteins/metabolism
Chemical Substances	CCCTC-Binding Factor ; CTCF protein, human ; Recombinant Fusion Proteins ; Repressor Proteins ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37) ; DNA methyltransferase 3A (EC 2.1.1.37) ; CRISPR-Associated Protein 9 (EC 3.1.-)
Language	English
Publishing date	2019-09-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-12166-w
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Article ; Online: GABPβ1L Wakes Up TERT.

Rahme, Gilbert J / Gaskell, Elizabeth / Bernstein, Bradley E

Cancer cell

2018 Volume 34, Issue 3, Page(s) 358–360

Abstract: TERT catalyzes telomere maintenance. While silenced in most normal somatic cells, TERT is expressed in cancer, often due to promoter mutations, facilitating replicative immortality. In this issue of Cancer Cell, Mancini et al. demonstrate that GABPβ1L is ...

Abstract	TERT catalyzes telomere maintenance. While silenced in most normal somatic cells, TERT is expressed in cancer, often due to promoter mutations, facilitating replicative immortality. In this issue of Cancer Cell, Mancini et al. demonstrate that GABPβ1L is required for mutant TERT promoter activity, thus identifying a potential therapeutic target.
MeSH term(s)	Glioblastoma ; Humans ; Mutation ; Promoter Regions, Genetic ; Protein Isoforms ; Telomerase/genetics
Chemical Substances	Protein Isoforms ; TERT protein, human (EC 2.7.7.49) ; Telomerase (EC 2.7.7.49)
Language	English
Publishing date	2018-09-09
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2018.08.011
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Zs.A 5650: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 104: Show issues

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Article ; Online: Single-cell and single-molecule epigenomics to uncover genome regulation at unprecedented resolution.

Shema, Efrat / Bernstein, Bradley E / Buenrostro, Jason D

Nature genetics

2018 Volume 51, Issue 1, Page(s) 19–25

Abstract: Recent advances in single-cell and single-molecule epigenomic technologies now enable the study of genome regulation and dynamics at unprecedented resolution. In this Perspective, we highlight some of these transformative technologies and discuss how ... ...

Abstract	Recent advances in single-cell and single-molecule epigenomic technologies now enable the study of genome regulation and dynamics at unprecedented resolution. In this Perspective, we highlight some of these transformative technologies and discuss how they have been used to identify new modes of gene regulation. We also contrast these assays with recent advances in single-cell transcriptomics and argue for the essential role of epigenomic technologies in both understanding cellular diversity and discovering gene regulatory mechanisms. In addition, we provide our view on the next generation of biological tools that we expect will open new avenues for elucidating the fundamental principles of gene regulation. Overall, this Perspective motivates the use of these high-resolution epigenomic technologies for mapping cell states and understanding regulatory diversity at single-molecule resolution within single cells.
MeSH term(s)	Animals ; Chromatin/genetics ; Epigenesis, Genetic/genetics ; Epigenomics/methods ; Gene Expression Regulation/genetics ; Genome/genetics ; Genomics/methods ; Humans ; Single-Cell Analysis/methods
Chemical Substances	Chromatin
Language	English
Publishing date	2018-12-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-018-0290-x
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 3613: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 46: Show issues

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Article ; Online: Integrative dissection of gene regulatory elements at base resolution.

Chen, Zeyu / Javed, Nauman / Moore, Molly / Wu, Jingyi / Sun, Gary / Vinyard, Michael / Collins, Alejandro / Pinello, Luca / Najm, Fadi J / Bernstein, Bradley E

Cell genomics

2023 Volume 3, Issue 6, Page(s) 100318

Abstract: Although vast numbers of putative gene regulatory elements have been cataloged, the sequence motifs and individual bases that underlie their functions remain largely unknown. Here, we combine epigenetic perturbations, base editing, and deep learning to ... ...

Abstract	Although vast numbers of putative gene regulatory elements have been cataloged, the sequence motifs and individual bases that underlie their functions remain largely unknown. Here, we combine epigenetic perturbations, base editing, and deep learning to dissect regulatory sequences within the exemplar immune locus encoding CD69. We converge on a ∼170 base interval within a differentially accessible and acetylated enhancer critical for CD69 induction in stimulated Jurkat T cells. Individual C-to-T base edits within the interval markedly reduce element accessibility and acetylation, with corresponding reduction of CD69 expression. The most potent base edits may be explained by their effect on regulatory interactions between the transcriptional activators GATA3 and TAL1 and the repressor BHLHE40. Systematic analysis suggests that the interplay between GATA3 and BHLHE40 plays a general role in rapid T cell transcriptional responses. Our study provides a framework for parsing regulatory elements in their endogenous chromatin contexts and identifying operative artificial variants.
Language	English
Publishing date	2023-04-28
Publishing country	United States
Document type	Journal Article
ISSN	2666-979X
ISSN (online)	2666-979X
DOI	10.1016/j.xgen.2023.100318
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Article ; Online: Epigenome editing strategies for the functional annotation of CTCF insulators

Daniel R. Tarjan / William A. Flavahan / Bradley E. Bernstein

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 8

Abstract: The role of CTCF-bound insulator elements in enhancer-gene interactions and transcriptional regulation remains poorly understood. Here, the authors investigate multiple epigenome editing strategies for perturbing individual CTCF-bound insulators, and ... ...

Abstract	The role of CTCF-bound insulator elements in enhancer-gene interactions and transcriptional regulation remains poorly understood. Here, the authors investigate multiple epigenome editing strategies for perturbing individual CTCF-bound insulators, and evaluate their effects on genome topology and transcription.
Keywords	Science ; Q
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
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Article ; Online: Epigenome editing strategies for the functional annotation of CTCF insulators

Daniel R. Tarjan / William A. Flavahan / Bradley E. Bernstein

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 8

Abstract	The role of CTCF-bound insulator elements in enhancer-gene interactions and transcriptional regulation remains poorly understood. Here, the authors investigate multiple epigenome editing strategies for perturbing individual CTCF-bound insulators, and evaluate their effects on genome topology and transcription.
Keywords	Science ; Q
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Chromatin complex dependencies reveal targeting opportunities in leukemia.

Najm, Fadi J / DeWeirdt, Peter / Moore, Molly M / Bevill, Samantha M / El Farran, Chadi A / Macias, Kevin A / Hegde, Mudra / Waterbury, Amanda L / Liau, Brian B / van Galen, Peter / Doench, John G / Bernstein, Bradley E

Nature communications

2023 Volume 14, Issue 1, Page(s) 448

Abstract: Chromatin regulators are frequently mutated in human cancer and are attractive drug targets. They include diverse proteins that share functional domains and assemble into related multi-subunit complexes. To investigate functional relationships among ... ...

Abstract	Chromatin regulators are frequently mutated in human cancer and are attractive drug targets. They include diverse proteins that share functional domains and assemble into related multi-subunit complexes. To investigate functional relationships among these regulators, here we apply combinatorial CRISPR knockouts (KOs) to test over 35,000 gene-gene pairings in leukemia cells, using a library of over 300,000 constructs. Top pairs that demonstrate either compensatory non-lethal interactions or synergistic lethality enrich for paralogs and targets that occupy the same protein complex. The screen highlights protein complex dependencies not apparent in single KO screens, for example MCM histone exchange, the nucleosome remodeling and deacetylase (NuRD) complex, and HBO1 (KAT7) complex. We explore two approaches to NuRD complex inactivation. Paralog and non-paralog combinations of the KAT7 complex emerge as synergistic lethal and specifically nominate the ING5 PHD domain as a potential therapeutic target when paired with other KAT7 complex member losses. These findings highlight the power of combinatorial screening to provide mechanistic insight and identify therapeutic targets within redundant networks.
MeSH term(s)	Humans ; Chromatin/genetics ; Mi-2 Nucleosome Remodeling and Deacetylase Complex/metabolism ; Chromatin Assembly and Disassembly ; Leukemia/drug therapy ; Leukemia/genetics ; Histone Acetyltransferases/metabolism
Chemical Substances	Chromatin ; Mi-2 Nucleosome Remodeling and Deacetylase Complex (EC 3.5.1.98) ; KAT7 protein, human (EC 2.3.1.48) ; Histone Acetyltransferases (EC 2.3.1.48)
Language	English
Publishing date	2023-01-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-36150-7
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