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Article ; Online: Long-distance association of topological boundaries through nuclear condensates.

Gamliel, Amir / Meluzzi, Dario / Oh, Soohwan / Jiang, Nan / Destici, Eugin / Rosenfeld, Michael G / Nair, Sreejith J

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 32, Page(s) e2206216119

Abstract: The eukaryotic genome is partitioned into distinct topological domains separated by boundary elements. Emerging data support the concept that several well-established nuclear compartments are ribonucleoprotein condensates assembled through the physical ... ...

Abstract	The eukaryotic genome is partitioned into distinct topological domains separated by boundary elements. Emerging data support the concept that several well-established nuclear compartments are ribonucleoprotein condensates assembled through the physical process of phase separation. Here, based on our demonstration that chemical disruption of nuclear condensate assembly weakens the insulation properties of a specific subset (∼20%) of topologically associated domain (TAD) boundaries, we report that the disrupted boundaries are characterized by a high level of transcription and striking spatial clustering. These topological boundary regions tend to be spatially associated, even interchromosomally, segregate with nuclear speckles, and harbor a specific subset of "housekeeping" genes widely expressed in diverse cell types. These observations reveal a previously unappreciated mode of genome organization mediated by conserved boundary elements harboring highly and widely expressed transcription units and associated transcriptional condensates.
MeSH term(s)	Cell Compartmentation ; Cell Nucleus/chemistry ; Cell Nucleus/genetics ; Cell Nucleus/metabolism ; Chromosomes/genetics ; Eukaryota/cytology ; Eukaryota/genetics ; Genes, Essential ; Genome/genetics ; Nuclear Speckles/genetics ; Ribonucleoproteins/metabolism ; Transcription, Genetic
Chemical Substances	Ribonucleoproteins
Language	English
Publishing date	2022-08-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2206216119
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Article ; Online: Spatially organized cellular communities form the developing human heart.

Nature

2024 Volume 627, Issue 8005, Page(s) 854–864

Abstract: The heart, which is the first organ to develop, is highly dependent on its form to ... ...

Abstract	The heart, which is the first organ to develop, is highly dependent on its form to function
MeSH term(s)	Animals ; Humans ; Mice ; Heart/anatomy & histology ; Heart/embryology ; Heart Diseases/metabolism ; Heart Diseases/pathology ; Heart Ventricles/anatomy & histology ; Heart Ventricles/cytology ; Heart Ventricles/embryology ; In Situ Hybridization, Fluorescence ; Models, Animal ; Myocardium/cytology ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/metabolism ; Single-Cell Gene Expression Analysis ; Body Patterning
Language	English
Publishing date	2024-03-13
Publishing country	England
Document type	Journal Article
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-024-07171-z
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Zs.A 26: 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)
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Article ; Online: Human-gained heart enhancers are associated with species-specific cardiac attributes.

Destici, Eugin / Zhu, Fugui / Tran, Shaina / Preissl, Sebastian / Farah, Elie N / Zhang, Yanxiao / Hou, Xiameng / Poirion, Olivier B / Lee, Ah Young / Grinstein, Jonathan D / Bloomekatz, Joshua / Kim, Hong Sook / Hu, Robert / Evans, Sylvia M / Ren, Bing / Benner, Chris / Chi, Neil C

Nature cardiovascular research

2022 Volume 1, Issue 9, Page(s) 830–843

Abstract: The heart, a vital organ which is first to develop, has adapted its size, structure and function in order to accommodate the circulatory demands for a broad range of animals. Although heart development is controlled by a relatively conserved network of ... ...

Abstract	The heart, a vital organ which is first to develop, has adapted its size, structure and function in order to accommodate the circulatory demands for a broad range of animals. Although heart development is controlled by a relatively conserved network of transcriptional/chromatin regulators, how the human heart has evolved species-specific features to maintain adequate cardiac output and function remains to be defined. Here, we show through comparative epigenomic analysis the identification of enhancers and promoters that have gained activity in humans during cardiogenesis. These cis-regulatory elements (CREs) are associated with genes involved in heart development and function, and may account for species-specific differences between human and mouse hearts. Supporting these findings, genetic variants that are associated with human cardiac phenotypic/disease traits, particularly those differing between human and mouse, are enriched in human-gained CREs. During early stages of human cardiogenesis, these CREs are also gained within genomic loci of transcriptional regulators, potentially expanding their role in human heart development. In particular, we discovered that gained enhancers in the locus of the early human developmental regulator
Language	English
Publishing date	2022-09-15
Publishing country	England
Document type	Journal Article
ISSN	2731-0590
ISSN (online)	2731-0590
DOI	10.1038/s44161-022-00124-7
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Article ; Online: Pluripotency factors functionally premark cell-type-restricted enhancers in ES cells.

Kim, Hong Sook / Tan, Yuliang / Ma, Wubin / Merkurjev, Daria / Destici, Eugin / Ma, Qi / Suter, Tom / Ohgi, Kenneth / Friedman, Meyer / Skowronska-Krawczyk, Dorota / Rosenfeld, Michael G

Nature

2018 Volume 556, Issue 7702, Page(s) 510–514

Abstract: Enhancers for embryonic stem (ES) cell-expressed genes and lineage-determining factors are characterized by conventional marks of enhancer activation in ES ... ...

Abstract	Enhancers for embryonic stem (ES) cell-expressed genes and lineage-determining factors are characterized by conventional marks of enhancer activation in ES cells
MeSH term(s)	Animals ; Cell Differentiation/genetics ; Enhancer Elements, Genetic ; Epigenesis, Genetic ; Female ; Gene Expression Regulation/genetics ; Macrophages/cytology ; Macrophages/metabolism ; Mice ; Mouse Embryonic Stem Cells/cytology ; Mouse Embryonic Stem Cells/metabolism ; Neural Stem Cells/cytology ; Neural Stem Cells/metabolism ; Organ Specificity ; Pluripotent Stem Cells/cytology ; Pluripotent Stem Cells/metabolism ; Reproducibility of Results ; Transcription Factors/metabolism
Chemical Substances	Transcription Factors
Language	English
Publishing date	2018-04-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-018-0048-8
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Zs.A 26: 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)
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Article ; Online: Mammalian cryptochromes impinge on cell cycle progression in a circadian clock-independent manner.

Destici, Eugin / Oklejewicz, Małgorzata / Saito, Shoko / van der Horst, Gijsbertus T J

Cell cycle (Georgetown, Tex.)

2011 Volume 10, Issue 21, Page(s) 3788–3797

Abstract: By gating cell cycle progression to specific times of the day, the intracellular circadian clock is thought to reduce the exposure of replicating cells to potentially hazardous environmental and endogenous genotoxic compounds. Although core clock gene ... ...

Abstract	By gating cell cycle progression to specific times of the day, the intracellular circadian clock is thought to reduce the exposure of replicating cells to potentially hazardous environmental and endogenous genotoxic compounds. Although core clock gene defects that eradicate circadian rhythmicity can cause an altered in vivo genotoxic stress response and aberrant proliferation rate, it remains to be determined to what extent these cell cycle related phenotypes are due to a cell-autonomous lack of circadian oscillations. We investigated the DNA damage sensitivity and proliferative capacity of cultured primary Cry1(-/- )\|Cry2(-/-) fibroblasts. Contrasting previous in vivo studies, we show that the absence of CRY proteins does not affect the cell-autonomous DNA damage response upon exposure of primary cells in vitro to genotoxic agents, but causes cells to proliferate faster. By comparing primary wild-type, Cry1(-/-) \|Cry2(-/-), Cry1(+/-)\|Cry2(-/-) and Cry1(-/-)\|Cry2(+/-) fibroblasts, we provide evidence that CRY proteins influence cell cycle progression in a cell-autonomous, but circadian clock-independent manner and that the accelerated cell cycle progression of Cry-deficient cells is caused by global dysregulation of Bmal1-dependent gene expression. These results suggest that the inconsistency between in vivo and in vitro observations might be attributed to systemic circadian control rather than a direct cell-autonomous control.
MeSH term(s)	Animals ; Cell Cycle/genetics ; Cell Proliferation ; Circadian Rhythm/genetics ; Cryptochromes/genetics ; Cryptochromes/physiology ; DNA Damage ; Gene Expression Regulation ; Mice ; Mice, Inbred C57BL
Chemical Substances	Cry1 protein, mouse ; Cry2 protein, mouse ; Cryptochromes
Language	English
Publishing date	2011-11-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.10.21.17974
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Zs.A 5881: Show issues

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Article ; Online: Altered phase-relationship between peripheral oscillators and environmental time in Cry1 or Cry2 deficient mouse models for early and late chronotypes.

Destici, Eugin / Jacobs, Edwin H / Tamanini, Filippo / Loos, Maarten / van der Horst, Gijsbertus T J / Oklejewicz, Małgorzata

PloS one

2013 Volume 8, Issue 12, Page(s) e83602

Abstract: The mammalian circadian system is composed of a light-entrainable central clock in the suprachiasmatic nuclei (SCN) of the brain and peripheral clocks in virtually any other tissue. It allows the organism to optimally adjust metabolic, physiological and ... ...

Abstract	The mammalian circadian system is composed of a light-entrainable central clock in the suprachiasmatic nuclei (SCN) of the brain and peripheral clocks in virtually any other tissue. It allows the organism to optimally adjust metabolic, physiological and behavioral functions to the physiological needs it will have at specific time of the day. According to the resonance theory, such rhythms are only advantageous to an organism when in tune with the environment, which is illustrated by the adverse health effects originating from chronic circadian disruption by jetlag and shift work. Using short-period Cry1 and long-period Cry2 deficient mice as models for morningness and eveningness, respectively, we explored the effect of chronotype on the phase relationship between the central SCN clock and peripheral clocks in other organs. Whereas the behavioral activity patterns and circadian gene expression in the SCN of light-entrained Cry1(-/-) and Cry2(-/-) mice largely overlapped with that of wild type mice, expression of clock and clock controlled genes in liver, kidney, small intestine, and skin was shown to be markedly phase-advanced or phase-delayed, respectively. Likewise, circadian rhythms in urinary corticosterone were shown to display a significantly altered phase relationship similar to that of gene expression in peripheral tissues. We show that the daily dissonance between peripheral clocks and the environment did not affect the lifespan of Cry1(-/-) or Cry2(-/-) mice. Nonetheless, the phase-shifted peripheral clocks in light-entrained mice with morningness and eveningness-like phenotypes may have implications for personalized preventive and therapeutic (i.e. chronomodulation-based) health care for people with early and late chronotypes.
MeSH term(s)	ARNTL Transcription Factors/genetics ; ARNTL Transcription Factors/metabolism ; Animals ; Circadian Rhythm/physiology ; Cryptochromes/deficiency ; Cryptochromes/genetics ; Environment ; Female ; Gene Expression Regulation ; Gene-Environment Interaction ; Longevity/genetics ; Male ; Mice ; Mice, Knockout ; Motor Activity/genetics ; Period Circadian Proteins/genetics ; Period Circadian Proteins/metabolism ; Suprachiasmatic Nucleus/physiology
Chemical Substances	ARNTL Transcription Factors ; Cry1 protein, mouse ; Cry2 protein, mouse ; Cryptochromes ; Per2 protein, mouse ; Period Circadian Proteins
Language	English
Publishing date	2013-12-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0083602
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Article ; Online: Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells.

Nature genetics

2019 Volume 51, Issue 9, Page(s) 1380–1388

Abstract: Chromatin architecture has been implicated in cell type-specific gene regulatory programs, yet how chromatin remodels during development remains to be fully elucidated. Here, by interrogating chromatin reorganization during human pluripotent stem cell ( ... ...

Abstract	Chromatin architecture has been implicated in cell type-specific gene regulatory programs, yet how chromatin remodels during development remains to be fully elucidated. Here, by interrogating chromatin reorganization during human pluripotent stem cell (hPSC) differentiation, we discover a role for the primate-specific endogenous retrotransposon human endogenous retrovirus subfamily H (HERV-H) in creating topologically associating domains (TADs) in hPSCs. Deleting these HERV-H elements eliminates their corresponding TAD boundaries and reduces the transcription of upstream genes, while de novo insertion of HERV-H elements can introduce new TAD boundaries. The ability of HERV-H to create TAD boundaries depends on high transcription, as transcriptional repression of HERV-H elements prevents the formation of boundaries. This ability is not limited to hPSCs, as these actively transcribed HERV-H elements and their corresponding TAD boundaries also appear in pluripotent stem cells from other hominids but not in more distantly related species lacking HERV-H elements. Overall, our results provide direct evidence for retrotransposons in actively shaping cell type- and species-specific chromatin architecture.
MeSH term(s)	Animals ; Cell Differentiation ; Chromatin/genetics ; Endogenous Retroviruses/genetics ; Gene Expression Regulation ; Humans ; Pluripotent Stem Cells/cytology ; Pluripotent Stem Cells/physiology ; Primates ; Response Elements ; Retroelements/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcription, Genetic
Chemical Substances	Chromatin ; Retroelements ; Transcription Factors
Language	English
Publishing date	2019-08-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-019-0479-7
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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)
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Article: Impact of the circadian clock on in vitro genotoxic risk assessment assays.

Destici, Eugin / Oklejewicz, Małgorzata / Nijman, Romana / Tamanini, Filippo / van der Horst, Gijsbertus T J

Mutation research

2009 Volume 680, Issue 1-2, Page(s) 87–94

Abstract: Our society expects safety assessment for drugs, chemicals, cosmetics, and foods, which to date cannot be achieved without the use of laboratory animals. At the same time, society aims at refining, reducing, and (ultimately) replacing animal testing. As ... ...

Abstract	Our society expects safety assessment for drugs, chemicals, cosmetics, and foods, which to date cannot be achieved without the use of laboratory animals. At the same time, society aims at refining, reducing, and (ultimately) replacing animal testing. As a consequence, much effort is taken to establish alternatives, such as toxicogenomics-based risk assessment assays on cultured cells and tissues. Evidently, the properties of cells in vitro will considerably differ from the in vivo situation. This review will discuss the impact of the circadian clock, an internal time keeping system that drives 24-h rhythms in metabolism, physiology and behavior, on in vitro genotoxic risk assessment. Our recent observation that DNA damaging agents can synchronize the circadian clock of individual cells in culture (and as a consequence the cyclic expression of clock-controlled genes, comprising up to 10% of the transcriptome) implies that the circadian clock should not be neglected when developing cell or tissue-based alternatives for chronic rodent toxicity assays.
MeSH term(s)	Animals ; Cells, Cultured ; Circadian Rhythm/drug effects ; Circadian Rhythm/physiology ; DNA Damage ; Humans ; Mutagenicity Tests ; Mutagens/classification ; Mutagens/toxicity ; Research Design ; Risk Assessment ; Time Factors
Chemical Substances	Mutagens
Language	English
Publishing date	2009-11
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	206607-5
ISSN	1873-135X ; 0027-5107 ; 1383-5718 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
ISSN (online)	1873-135X
ISSN	0027-5107 ; 1383-5718 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
DOI	10.1016/j.mrgentox.2009.09.001
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Article: Phase resetting of the mammalian circadian clock by DNA damage.

Oklejewicz, Małgorzata / Destici, Eugin / Tamanini, Filippo / Hut, Roelof A / Janssens, Roel / van der Horst, Gijsbertus T J

Current biology : CB

2008 Volume 18, Issue 4, Page(s) 286–291

Abstract: To anticipate the momentum of the day, most organisms have developed an internal clock that drives circadian rhythms in metabolism, physiology, and behavior [1]. Recent studies indicate that cell-cycle progression and DNA-damage-response pathways are ... ...

Abstract	To anticipate the momentum of the day, most organisms have developed an internal clock that drives circadian rhythms in metabolism, physiology, and behavior [1]. Recent studies indicate that cell-cycle progression and DNA-damage-response pathways are under circadian control [2-4]. Because circadian output processes can feed back into the clock, we investigated whether DNA damage affects the mammalian circadian clock. By using Rat-1 fibroblasts expressing an mPer2 promoter-driven luciferase reporter, we show that ionizing radiation exclusively phase advances circadian rhythms in a dose- and time-dependent manner. Notably, this in vitro finding translates to the living animal, because ionizing radiation also phase advanced behavioral rhythms in mice. The underlying mechanism involves ATM-mediated damage signaling as radiation-induced phase shifting was suppressed in fibroblasts from cancer-predisposed ataxia telangiectasia and Nijmegen breakage syndrome patients. Ionizing radiation-induced phase shifting depends on neither upregulation or downregulation of clock gene expression nor on de novo protein synthesis and, thus, differs mechanistically from dexamethasone- and forskolin-provoked clock resetting [5]. Interestingly, ultraviolet light and tert-butyl hydroperoxide also elicited a phase-advancing effect. Taken together, our data provide evidence that the mammalian circadian clock, like that of the lower eukaryote Neurospora[6], responds to DNA damage and suggest that clock resetting is a universal property of DNA damage.
MeSH term(s)	Animals ; Ataxia Telangiectasia Mutated Proteins ; Biological Clocks/drug effects ; Biological Clocks/genetics ; Biological Clocks/radiation effects ; Cell Cycle Proteins/metabolism ; Cell Line ; Circadian Rhythm/drug effects ; Circadian Rhythm/radiation effects ; DNA Damage ; DNA-Binding Proteins/metabolism ; Gamma Rays/adverse effects ; Gene Expression/drug effects ; Gene Expression/radiation effects ; Male ; Mice ; Mice, Inbred C57BL ; Protein-Serine-Threonine Kinases/metabolism ; Rats ; Signal Transduction/radiation effects ; Tumor Suppressor Proteins/metabolism
Chemical Substances	Cell Cycle Proteins ; DNA-Binding Proteins ; Tumor Suppressor Proteins ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Atm protein, mouse (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2008-02-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2008.01.047
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