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Artikel ; Online: Suv39h-catalyzed H3K9me3 is critical for euchromatic genome organization and the maintenance of gene transcription.

Keenan, Christine R / Coughlan, Hannah D / Iannarella, Nadia / Tapia Del Fierro, Andres / Keniry, Andrew / Johanson, Timothy M / Chan, Wing Fuk / Garnham, Alexandra L / Whitehead, Lachlan W / Blewitt, Marnie E / Smyth, Gordon K / Allan, Rhys S

Genome research

2024 Band 34, Heft 4, Seite(n) 556–571

Abstract: H3K9me3-dependent heterochromatin is critical for the silencing of repeat-rich pericentromeric regions and also has key roles in repressing lineage-inappropriate protein-coding genes in differentiation and development. Here, we investigate the molecular ... ...

Abstract	H3K9me3-dependent heterochromatin is critical for the silencing of repeat-rich pericentromeric regions and also has key roles in repressing lineage-inappropriate protein-coding genes in differentiation and development. Here, we investigate the molecular consequences of heterochromatin loss in cells deficient in both SUV39H1 and SUV39H2 (Suv39DKO), the major mammalian histone methyltransferase enzymes that catalyze heterochromatic H3K9me3 deposition. We reveal a paradoxical repression of protein-coding genes in Suv39DKO cells, with these differentially expressed genes principally in euchromatic (Tn5-accessible, H3K4me3- and H3K27ac-marked) rather than heterochromatic (H3K9me3-marked) or polycomb (H3K27me3-marked) regions. Examination of the three-dimensional (3D) nucleome reveals that transcriptomic dysregulation occurs in euchromatic regions close to the nuclear periphery in 3D space. Moreover, this transcriptomic dysregulation is highly correlated with altered 3D genome organization in Suv39DKO cells. Together, our results suggest that the nuclear lamina-tethering of Suv39-dependent H3K9me3 domains provides an essential scaffold to support euchromatic genome organization and the maintenance of gene transcription for healthy cellular function.
Mesh-Begriff(e)	Euchromatin/metabolism ; Euchromatin/genetics ; Histones/metabolism ; Histones/genetics ; Methyltransferases/metabolism ; Methyltransferases/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Histone-Lysine N-Methyltransferase/genetics ; Heterochromatin/metabolism ; Heterochromatin/genetics ; Transcription, Genetic ; Repressor Proteins/metabolism ; Repressor Proteins/genetics ; Animals ; Mice ; Humans ; Gene Expression Regulation ; Cell Line
Sprache	Englisch
Erscheinungsdatum	2024-05-15
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	1284872-4
ISSN	1549-5469 ; 1088-9051 ; 1054-9803
ISSN (online)	1549-5469
ISSN	1088-9051 ; 1054-9803
DOI	10.1101/gr.279119.124
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Activation of stably silenced genes by recruitment of a synthetic de-methylating module.

Chan, Wing Fuk / Coughlan, Hannah D / Chen, Yunshun / Keenan, Christine R / Smyth, Gordon K / Perkins, Andrew C / Johanson, Timothy M / Allan, Rhys S

Nature communications

2022 Band 13, Heft 1, Seite(n) 5582

Abstract: Stably silenced genes that display a high level of CpG dinucleotide methylation are refractory to the current generation of dCas9-based activation systems. To counter this, we create an improved activation system by coupling the catalytic domain of DNA ... ...

Abstract	Stably silenced genes that display a high level of CpG dinucleotide methylation are refractory to the current generation of dCas9-based activation systems. To counter this, we create an improved activation system by coupling the catalytic domain of DNA demethylating enzyme TET1 with transcriptional activators (TETact). We show that TETact demethylation-coupled activation is able to induce transcription of suppressed genes, both individually and simultaneously in cells, and has utility across a number of cell types. Furthermore, we show that TETact can effectively reactivate embryonic haemoglobin genes in non-erythroid cells. We anticipate that TETact will expand the existing CRISPR toolbox and be valuable for functional studies, genetic screens and potential therapeutics.
Mesh-Begriff(e)	CRISPR-Cas Systems ; Clustered Regularly Interspaced Short Palindromic Repeats ; DNA Methylation ; Epigenesis, Genetic ; Promoter Regions, Genetic/genetics ; Transcription Factors/metabolism ; Transcriptional Activation
Chemische Substanzen	Transcription Factors
Sprache	Englisch
Erscheinungsdatum	2022-09-23
Erscheinungsland	England
Dokumenttyp	Journal Article ; 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/s41467-022-33181-4
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Survey of activation-induced genome architecture reveals a novel enhancer of Myc.

Chan, Wing Fuk / Coughlan, Hannah D / Ruhle, Michelle / Iannarella, Nadia / Alvarado, Carolina / Groom, Joanna R / Keenan, Christine R / Kueh, Andrew J / Wheatley, Adam K / Smyth, Gordon K / Allan, Rhys S / Johanson, Timothy M

Immunology and cell biology

2023 Band 101, Heft 4, Seite(n) 345–357

Abstract: The transcription factor Myc is critically important in driving cell proliferation, a function that is frequently dysregulated in cancer. To avoid this dysregulation Myc is tightly controlled by numerous layers of regulation. One such layer is the use of ...

Abstract	The transcription factor Myc is critically important in driving cell proliferation, a function that is frequently dysregulated in cancer. To avoid this dysregulation Myc is tightly controlled by numerous layers of regulation. One such layer is the use of distal regulatory enhancers to drive Myc expression. Here, using chromosome conformation capture to examine B cells of the immune system in the first hours after their activation, we reveal a previously unidentified enhancer of Myc. The interactivity of this enhancer coincides with a dramatic, but discrete, spike in Myc expression 3 h post-activation. However, genetic deletion of this region, has little impact on Myc expression, Myc protein level or in vitro and in vivo cell proliferation. Examination of the enhancer deleted regulatory landscape suggests that enhancer redundancy likely sustains Myc expression. This work highlights not only the importance of temporally examining enhancers, but also the complexity and dynamics of the regulation of critical genes such as Myc.
Mesh-Begriff(e)	Genes, myc ; Enhancer Elements, Genetic/genetics ; Transcription Factors/metabolism ; Gene Expression Regulation ; Promoter Regions, Genetic
Chemische Substanzen	Transcription Factors
Sprache	Englisch
Erscheinungsdatum	2023-02-14
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	284057-1
ISSN	1440-1711 ; 0818-9641
ISSN (online)	1440-1711
ISSN	0818-9641
DOI	10.1111/imcb.12626
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Three-dimensional genome architecture coordinates key regulators of lineage specification in mammary epithelial cells.

Milevskiy, Michael J G / Coughlan, Hannah D / Kane, Serena R / Johanson, Timothy M / Kordafshari, Somayeh / Chan, Wing Fuk / Tsai, Minhsuang / Surgenor, Elliot / Wilcox, Stephen / Allan, Rhys S / Chen, Yunshun / Lindeman, Geoffrey J / Smyth, Gordon K / Visvader, Jane E

Cell genomics

2023 Band 3, Heft 11, Seite(n) 100424

Abstract: Although lineage-specific genes have been identified in the mammary gland, little is known about the contribution of the 3D genome organization to gene regulation in the epithelium. Here, we describe the chromatin landscape of the three major epithelial ... ...

Abstract	Although lineage-specific genes have been identified in the mammary gland, little is known about the contribution of the 3D genome organization to gene regulation in the epithelium. Here, we describe the chromatin landscape of the three major epithelial subsets through integration of long- and short-range chromatin interactions, accessibility, histone modifications, and gene expression. While basal genes display exquisite lineage specificity via distal enhancers, luminal-specific genes show widespread promoter priming in basal cells. Cell specificity in luminal progenitors is largely mediated through extensive chromatin interactions with super-enhancers in gene-body regions in addition to interactions with polycomb silencer elements. Moreover, lineage-specific transcription factors appear to be controlled through cell-specific chromatin interactivity. Finally, chromatin accessibility rather than interactivity emerged as a defining feature of the activation of quiescent basal stem cells. This work provides a comprehensive resource for understanding the role of higher-order chromatin interactions in cell-fate specification and differentiation in the adult mouse mammary gland.
Sprache	Englisch
Erscheinungsdatum	2023-10-16
Erscheinungsland	United States
Dokumenttyp	Journal Article
ISSN	2666-979X
ISSN (online)	2666-979X
DOI	10.1016/j.xgen.2023.100424
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Identification and characterization of the long noncoding RNA Dreg1 as a novel regulator of Gata3.

Chan, Wing Fuk / Coughlan, Hannah D / Iannarella, Nadia / Smyth, Gordon K / Johanson, Timothy M / Keenan, Christine R / Allan, Rhys S

Immunology and cell biology

2020 Band 99, Heft 3, Seite(n) 323–332

Abstract: The eukaryotic genome is three-dimensionally segregated into discrete globules of topologically associating domains (TADs), within which numerous cis-regulatory elements such as enhancers and promoters interact to regulate gene expression. In this study, ...

Abstract	The eukaryotic genome is three-dimensionally segregated into discrete globules of topologically associating domains (TADs), within which numerous cis-regulatory elements such as enhancers and promoters interact to regulate gene expression. In this study, we identify a T-cell-specific sub-TAD containing the Gata3 locus, and reveal a previously uncharacterized long noncoding RNA (Dreg1) within a distant enhancer lying approximately 280 kb downstream of Gata3. Dreg1 expression is highly correlated with that of Gata3 during early immune system development and T helper type 2 cell differentiation. Inhibition and overexpression of Dreg1 suggest that it may be involved in the establishment, but not in the maintenance of Gata3 expression. Overall, we propose that Dreg1 is a novel regulator of Gata3 and may inform therapeutic strategies in diseases such allergy and lymphoma, where Gata3 has a pathological role.
Mesh-Begriff(e)	Chromatin ; Enhancer Elements, Genetic/genetics ; GATA3 Transcription Factor/genetics ; GATA3 Transcription Factor/metabolism ; Promoter Regions, Genetic ; RNA, Long Noncoding/genetics
Chemische Substanzen	Chromatin ; GATA3 Transcription Factor ; RNA, Long Noncoding
Sprache	Englisch
Erscheinungsdatum	2020-10-17
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	284057-1
ISSN	1440-1711 ; 0818-9641
ISSN (online)	1440-1711
ISSN	0818-9641
DOI	10.1111/imcb.12408
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Multi-level remodelling of chromatin underlying activation of human T cells.

Bediaga, Naiara G / Coughlan, Hannah D / Johanson, Timothy M / Garnham, Alexandra L / Naselli, Gaetano / Schröder, Jan / Fearnley, Liam G / Bandala-Sanchez, Esther / Allan, Rhys S / Smyth, Gordon K / Harrison, Leonard C

Scientific reports

2021 Band 11, Heft 1, Seite(n) 528

Abstract: Remodelling of chromatin architecture is known to regulate gene expression and has been well characterized in cell lineage development but less so in response to cell perturbation. Activation of T cells, which triggers extensive changes in ... ...

Abstract	Remodelling of chromatin architecture is known to regulate gene expression and has been well characterized in cell lineage development but less so in response to cell perturbation. Activation of T cells, which triggers extensive changes in transcriptional programs, serves as an instructive model to elucidate how changes in chromatin architecture orchestrate gene expression in response to cell perturbation. To characterize coordinate changes at different levels of chromatin architecture, we analyzed chromatin accessibility, chromosome conformation and gene expression in activated human T cells. T cell activation was characterized by widespread changes in chromatin accessibility and interactions that were shared between activated CD4
Mesh-Begriff(e)	CD4-Positive T-Lymphocytes ; CD8-Positive T-Lymphocytes ; Cells, Cultured ; Chromatin/chemistry ; Chromatin/genetics ; Chromatin Assembly and Disassembly/genetics ; Chromatin Assembly and Disassembly/physiology ; Gene Expression Regulation, Developmental/genetics ; Humans ; Lymphocyte Activation/genetics ; Male ; Nucleosomes/genetics ; T-Lymphocytes/immunology ; Transcription Factors ; Transcription, Genetic/genetics
Chemische Substanzen	Chromatin ; Nucleosomes ; Transcription Factors
Sprache	Englisch
Erscheinungsdatum	2021-01-12
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-80165-9
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Pre-mitotic genome re-organisation bookends the B cell differentiation process.

Chan, Wing Fuk / Coughlan, Hannah D / Zhou, Jie H S / Keenan, Christine R / Bediaga, Naiara G / Hodgkin, Philip D / Smyth, Gordon K / Johanson, Timothy M / Allan, Rhys S

Nature communications

2021 Band 12, Heft 1, Seite(n) 1344

Abstract: During cellular differentiation chromosome conformation is intricately remodelled to support the lineage-specific transcriptional programs required for initiating and maintaining lineage identity. When these changes occur in relation to cell cycle, ... ...

Abstract	During cellular differentiation chromosome conformation is intricately remodelled to support the lineage-specific transcriptional programs required for initiating and maintaining lineage identity. When these changes occur in relation to cell cycle, division and time in response to cellular activation and differentiation signals has yet to be explored, although it has been proposed to occur during DNA synthesis or after mitosis. Here, we elucidate the chromosome conformational changes in B lymphocytes as they differentiate and expand from a naive, quiescent state into antibody secreting plasma cells. We find gene-regulatory chromosome reorganization in late G1 phase before the first division, and that this configuration is remarkably stable as the cells massively and rapidly clonally expand. A second wave of conformational change occurs as cells terminally differentiate into plasma cells, coincident with increased time in G1 phase. These results provide further explanation for how lymphocyte fate is imprinted prior to the first division. They also suggest that chromosome reconfiguration occurs prior to DNA replication and mitosis, and is linked to a gene expression program that controls the differentiation process required for the generation of immunity.
Mesh-Begriff(e)	Animals ; Antibody-Producing Cells ; B-Lymphocytes/physiology ; Cell Cycle ; Cell Differentiation/genetics ; Cell Differentiation/physiology ; Cell Division ; Chromatin ; Chromosomes ; DNA Replication ; Epigenomics ; G1 Phase/genetics ; Gene Expression Regulation ; Genome ; Lymphocyte Activation/genetics ; Lymphocyte Activation/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitosis ; Plasma Cells
Chemische Substanzen	Chromatin
Sprache	Englisch
Erscheinungsdatum	2021-02-26
Erscheinungsland	England
Dokumenttyp	Journal Article ; 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/s41467-021-21536-2
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Transcription-factor-mediated supervision of global genome architecture maintains B cell identity.

Johanson, Timothy M / Lun, Aaron T L / Coughlan, Hannah D / Tan, Tania / Smyth, Gordon K / Nutt, Stephen L / Allan, Rhys S

Nature immunology

2018 Band 19, Heft 11, Seite(n) 1257–1264

Abstract: Recent studies have elucidated cell-lineage-specific three-dimensional genome organization; however, how such specific architecture is established or maintained is unclear. We hypothesized that lineage-defining transcription factors maintain cell ... ...

Abstract	Recent studies have elucidated cell-lineage-specific three-dimensional genome organization; however, how such specific architecture is established or maintained is unclear. We hypothesized that lineage-defining transcription factors maintain cell identity via global control of genome organization. These factors bind many genomic sites outside of the genes that they directly regulate and thus are potentially implicated in three-dimensional genome organization. Using chromosome-conformation-capture techniques, we show that the transcription factor Paired box 5 (Pax5) is critical for the establishment and maintenance of the global lineage-specific architecture of B cells. Pax5 was found to supervise genome architecture throughout B cell differentiation, until the plasmablast stage, in which Pax5 is naturally silenced and B cell-specific genome structure is lost. Crucially, Pax5 did not rely on ongoing transcription to organize the genome. These results implicate sequence-specific DNA-binding proteins in global genome organization to establish and maintain lineage fidelity.
Mesh-Begriff(e)	Animals ; B-Lymphocytes/cytology ; B-Lymphocytes/metabolism ; Cell Differentiation/genetics ; Cell Lineage/genetics ; Male ; Mice ; Mice, Inbred C57BL ; PAX5 Transcription Factor/genetics ; PAX5 Transcription Factor/metabolism
Chemische Substanzen	PAX5 Transcription Factor ; Pax5 protein, mouse
Sprache	Englisch
Erscheinungsdatum	2018-10-15
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-018-0234-8
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Chromosomes distribute randomly to, but not within, human neutrophil nuclear lobes.

Keenan, Christine R / Mlodzianoski, Michael J / Coughlan, Hannah D / Bediaga, Naiara G / Naselli, Gaetano / Lucas, Erin C / Wang, Qike / de Graaf, Carolyn A / Hilton, Douglas J / Harrison, Leonard C / Smyth, Gordon K / Rogers, Kelly L / Boudier, Thomas / Allan, Rhys S / Johanson, Timothy M

iScience

2021 Band 24, Heft 3, Seite(n) 102161

Abstract: The proximity pattern and radial distribution of chromosome territories within spherical nuclei are random and non-random, respectively. Whether this distribution pattern is conserved in the partitioned or lobed nuclei of polymorphonuclear cells is ... ...

Abstract	The proximity pattern and radial distribution of chromosome territories within spherical nuclei are random and non-random, respectively. Whether this distribution pattern is conserved in the partitioned or lobed nuclei of polymorphonuclear cells is unclear. Here we use chromosome paint technology to examine the chromosome territories of all 46 chromosomes in hundreds of single human neutrophils - an abundant and famously polymorphonuclear immune cell. By comparing the distribution of chromosomes to randomly shuffled controls and validating with orthogonal chromosome conformation capture technology, we show for the first time that human chromosomes randomly distribute to neutrophil nuclear lobes, while maintaining a non-random radial distribution within these lobes. Furthermore, we demonstrate that chromosome length correlates with three-dimensional volume not only in neutrophils but other human immune cells. This work demonstrates that chromosomes are largely passive passengers during the neutrophil lobing process but are able to subsequently maintain their macro-level organization within lobes.
Sprache	Englisch
Erscheinungsdatum	2021-02-07
Erscheinungsland	United States
Dokumenttyp	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2021.102161
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Type 1 conventional dendritic cell fate and function are controlled by DC-SCRIPT.

Zhang, Shengbo / Coughlan, Hannah D / Ashayeripanah, Mitra / Seizova, Simona / Kueh, Andrew J / Brown, Daniel V / Cao, Wang / Jacquelot, Nicolas / D'Amico, Angela / Lew, Andrew M / Zhan, Yifan / Tonkin, Christopher J / Villadangos, Jose A / Smyth, Gordon K / Chopin, Michaël / Nutt, Stephen L

Science immunology

2021 Band 6, Heft 58

Abstract: The functional diversification of dendritic cells (DCs) is a key step in establishing protective immune responses. Despite the importance of DC lineage diversity, its genetic basis is not fully understood. The transcription factor DC-SCRIPT is expressed ... ...

Abstract	The functional diversification of dendritic cells (DCs) is a key step in establishing protective immune responses. Despite the importance of DC lineage diversity, its genetic basis is not fully understood. The transcription factor DC-SCRIPT is expressed in conventional DCs (cDCs) and their committed bone marrow progenitors but not in plasmacytoid DCs (pDCs). We show that mice lacking DC-SCRIPT displayed substantially impaired development of IRF8 (interferon regulatory factor 8)-dependent cDC1, whereas cDC2 numbers increased marginally. The residual DC-SCRIPT-deficient cDC1s had impaired capacity to capture and present cell-associated antigens and to secrete IL-12p40, two functional hallmarks of this population. Genome-wide mapping of DC-SCRIPT binding and gene expression analyses revealed a key role for DC-SCRIPT in maintaining cDC1 identity via the direct regulation of cDC1 signature genes, including
Mesh-Begriff(e)	Animals ; Bone Marrow Transplantation ; Cell Differentiation/genetics ; Cell Differentiation/immunology ; Cells, Cultured ; Cross-Priming/genetics ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Disease Models, Animal ; Female ; Fibroblasts ; Gene Expression Regulation/immunology ; Humans ; Interferon Regulatory Factors/genetics ; Interferon Regulatory Factors/metabolism ; Interleukin-12/metabolism ; Male ; Mice ; Mice, Knockout ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Toxoplasma/immunology ; Toxoplasmosis/blood ; Toxoplasmosis/immunology ; Toxoplasmosis/parasitology ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transplantation Chimera
Chemische Substanzen	DC-SCRIPT protein, mouse ; DNA-Binding Proteins ; Interferon Regulatory Factors ; Nuclear Proteins ; Transcription Factors ; interferon regulatory factor-8 ; Interleukin-12 (187348-17-0)
Sprache	Englisch
Erscheinungsdatum	2021-04-02
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.abf4432
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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