scholarly journals ATPase SRCAP is a new player in cell division, uncovering molecular aspects of Floating-Harbor syndrome

2020 ◽  
Author(s):  
Giovanni Messina ◽  
Yuri Prozzillo ◽  
Francesca Delle Monache ◽  
Maria Virginia Santopietro ◽  
Maria Teresa Atterrato ◽  
...  
Keyword(s):  
Cell Division ◽  
Chromatin Remodeling ◽  
Catalytic Subunit ◽  
Current View ◽  
Mitotic Apparatus ◽  
Direct Role ◽  
The Core ◽  
Chromatin Remodeling Complex ◽  
Evolutionarily Conserved ◽  
Floating Harbor Syndrome

AbstractFloating-Harbor syndrome (FHS) is a rare genetic disease affecting human development caused by heterozygous truncating mutations in the Srcap gene, which encodes the ATPase SRCAP, the core catalytic subunit of the homonymous chromatin-remodeling complex. Using a combined approach, we studied the involvement of SRCAP protein in cell cycle progression in HeLa cells. In addition to the canonical localization in interphase nuclei, both SRCAP and its Drosophila orthologue DOMINO-A localized to the mitotic apparatus after nuclear envelope breakdown. Moreover, SRCAP and DOMINO-A depletion impaired mitosis and cytokinesis in human and Drosophila cells, respectively. Importantly, SRCAP interacted with several cytokinesis regulators at telophase, strongly supporting a direct role in cytokinesis, independent of its chromatin remodeling functions. Our results provide clues about previously undetected, evolutionarily conserved roles of SRCAP in ensuring proper mitosis and cytokinesis. We propose that perturbations in cell division contribute to the onset of developmental defects characteristic of FHS.SummarySignificance statementSrcap is the causative gene of the rare Floating Harbor syndrome (FHS). It encodes the ATPase SRCAP, the core catalytic subunit of the homonymous multiprotein chromatin-remodeling complex in humans, which promotes the exchange of canonical histone H2A with the H2A.Z variant. According to the current view on SRCAP protein functions, FHS is caused by chromatin remodeling defects. Our findings suggest that, in addition to the established function as epigenetic regulator, SRCAP plays previously undetected and evolutionarily conserved roles in cell division. Hence, we propose that perturbations in cell division produced by SRCAP mutations are important causative factors co-occurring at the onset of FHS.

scholarly journals The ATPase SRCAP is associated with the mitotic apparatus, uncovering novel molecular aspects of Floating-Harbor syndrome

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Giovanni Messina ◽  
Yuri Prozzillo ◽  
Francesca Delle Monache ◽  
Maria Virginia Santopietro ◽  
Maria Teresa Atterrato ◽  
...  
Keyword(s):  
Cell Division ◽  
Chromatin Remodeling ◽  
Cell Biology ◽  
Cell Cycle Progression ◽  
Reverse Genetics ◽  
Genetic Diseases ◽  
Main Function ◽  
Histone H2a ◽  
Mitotic Apparatus ◽  
Floating Harbor Syndrome

Abstract Background A variety of human genetic diseases is known to be caused by mutations in genes encoding chromatin factors and epigenetic regulators, such as DNA or histone modifying enzymes and members of ATP-dependent chromatin remodeling complexes. Floating-Harbor syndrome is a rare genetic disease affecting human development caused by dominant truncating mutations in the SRCAP gene, which encodes the ATPase SRCAP, the core catalytic subunit of the homonymous chromatin-remodeling complex. The main function of the SRCAP complex is to promote the exchange of histone H2A with the H2A.Z variant. According to the canonical role played by the SRCAP protein in epigenetic regulation, the Floating-Harbor syndrome is thought to be a consequence of chromatin perturbations. However, additional potential physiological functions of SRCAP have not been sufficiently explored. Results We combined cell biology, reverse genetics, and biochemical approaches to study the subcellular localization of the SRCAP protein and assess its involvement in cell cycle progression in HeLa cells. Surprisingly, we found that SRCAP associates with components of the mitotic apparatus (centrosomes, spindle, midbody), interacts with a plethora of cytokinesis regulators, and positively regulates their recruitment to the midbody. Remarkably, SRCAP depletion perturbs both mitosis and cytokinesis. Similarly, DOM-A, the functional SRCAP orthologue in Drosophila melanogaster, is found at centrosomes and the midbody in Drosophila cells, and its depletion similarly affects both mitosis and cytokinesis. Conclusions Our findings provide first evidence suggesting that SRCAP plays previously undetected and evolutionarily conserved roles in cell division, independent of its functions in chromatin regulation. SRCAP may participate in two different steps of cell division: by ensuring proper chromosome segregation during mitosis and midbody function during cytokinesis. Moreover, our findings emphasize a surprising scenario whereby alterations in cell division produced by SRCAP mutations may contribute to the onset of Floating-Harbor syndrome.

scholarly journals Sfh1p, a component of a novel chromatin-remodeling complex, is required for cell cycle progression.

1997 ◽  
Vol 17 (6) ◽  
pp. 3323-3334 ◽  
Author(s):  
Y Cao ◽  
B R Cairns ◽  
R D Kornberg ◽  
B C Laurent
Keyword(s):  
Cell Cycle ◽  
Chromatin Remodeling ◽  
Cell Cycle Progression ◽  
Normal Function ◽  
Temperature Sensitive ◽  
Cycle Progression ◽  
Conserved Domain ◽  
Chromatin Remodeling Complex ◽  
Evolutionarily Conserved ◽  
M Phase

Several eukaryotic multiprotein complexes, including the Saccharomyces cerevisiae Snf/Swi complex, remodel chromatin for transcription. In contrast to the Snf/Swi proteins, Sfh1p, a new Snf5p paralog, is essential for viability. The evolutionarily conserved domain of Sfh1p is sufficient for normal function, and Sfh1p interacts functionally and physically with an essential Snf2p paralog in a novel nucleosome-restructuring complex called RSC (for remodels the structure of chromatin). A temperature-sensitive sfh1 allele arrests cells in the G2/M phase of the cell cycle, and the Sfh1 protein is specifically phosphorylated in the G1 phase. Together, these results demonstrate a link between chromatin remodeling and progression through the cell division cycle, providing genetic clues to possible targets for RSC function.

scholarly journals SWI/SNF remains localized to chromatin in the presence of SCHLAP1

2018 ◽  
Author(s):  
Jesse R. Raab ◽  
Keriayn N. Smith ◽  
Camarie C. Spear ◽  
Carl J. Manner ◽  
J. Mauro Calabrese ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Chromatin Remodeling ◽  
Histone Modifications ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Metastatic Prostate Cancer ◽  
The Core ◽  
Prostate Cells ◽  
Chromatin Remodeling Complex ◽  
Non Coding Rnas

AbstractSCHLAP1 is a long-noncoding RNA that is prognostic for progression to metastatic prostate cancer and promotes an invasive phenotype. SCHLAP1 is reported to function by depleting the core SWI/SNF subunit, SMARCB1, from the genome. SWI/SNF is a large, multi-subunit, chromatin remodeling complex that can be combinatorially assembled to yield hundreds to thousands of distinct complexes. Here, we investigated the hypothesis that SCHLAP1 affects only specific forms of SWI/SNF and that the remaining SWI/SNF complexes were important for the increased invasion in SCHLAP1 expressing prostate cells. Using several assays we found that SWI/SNF is not depleted from the genome by SCHLAP1 expression. We find that SCHLAP1 induces changes to chromatin openness but is not sufficient to drive changes in histone modifications. Additionally, we show that SWI/SNF binds many coding and non-coding RNAs. Together these results suggest that SCHLAP1 has roles independent of canonical SWI/SNF and that SWI/SNF broadly interacts with RNA.

scholarly journals Piwi suppresses transcription of Brahma-dependent transposons via Maelstrom in ovarian somatic cells

2020 ◽  
Vol 6 (50) ◽  
pp. eaaz7420
Author(s):  
Ryo Onishi ◽  
Kaoru Sato ◽  
Kensaku Murano ◽  
Lumi Negishi ◽  
Haruhiko Siomi ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Chromatin Remodeling ◽  
Adenosine Triphosphatase ◽  
Somatic Cells ◽  
Pol Ii ◽  
Heterochromatin Formation ◽  
Rna Transcripts ◽  
The Core ◽  
Chromatin Remodeling Complex

Drosophila Piwi associates with PIWI-interacting RNAs (piRNAs) and represses transposons transcriptionally through heterochromatinization; however, this process is poorly understood. Here, we identify Brahma (Brm), the core adenosine triphosphatase of the SWI/SNF chromatin remodeling complex, as a new Piwi interactor, and show Brm involvement in activating transcription of Piwi-targeted transposons before silencing. Bioinformatic analyses indicated that Piwi, once bound to target RNAs, reduced the occupancies of SWI/SNF and RNA polymerase II (Pol II) on target loci, abrogating transcription. Artificial piRNA-driven targeting of Piwi to RNA transcripts enhanced repression of Brm-dependent reporters compared with Brm-independent reporters. This was dependent on Piwi cofactors, Gtsf1/Asterix (Gtsf1), Panoramix/Silencio (Panx), and Maelstrom (Mael), but not Eggless/dSetdb (Egg)–mediated H3K9me3 deposition. The λN-box B–mediated tethering of Mael to reporters repressed Brm-dependent genes in the absence of Piwi, Panx, and Gtsf1. We propose that Piwi, via Mael, can rapidly suppress transcription of Brm-dependent genes to facilitate heterochromatin formation.

scholarly journals Mammalian SWI/SNF collaborates with a polycomb-associated protein to regulate male germ line transcription in the mouse

2018 ◽  
Author(s):  
Debashish U. Menon ◽  
Yoichiro Shibata ◽  
Weipeng Mu ◽  
Terry Magnuson
Keyword(s):  
Chromatin Remodeling ◽  
Germ Line ◽  
Chromatin Accessibility ◽  
Catalytic Subunit ◽  
Histone H2a ◽  
Meiotic Progression ◽  
Chromatin Remodeling Complex ◽  
Epigenetic Modifiers ◽  
Summary Statement ◽  
Target Promoters

AbstractA deficiency in BRG1, the catalytic subunit of the SWI/SNF chromatin remodeling complex, results in a meiotic arrest during spermatogenesis. Here, we explore the causative mechanisms. BRG1 is preferentially enriched at active promoters of genes essential for spermatogonial pluripotency and meiosis. In contrast, BRG1 is also associated with the repression of somatic genes. Chromatin accessibility at these target promoters is dependent upon BRG1. These results favor a model where BRG1 coordinates spermatogenic transcription to ensure meiotic progression. In spermatocytes, BRG1 interacts with SCML2, a testes specific PRC1 factor that is associated with the repression of somatic genes. We present evidence to suggest that BRG1 and SCML2 concordantly regulate genes during meiosis. Furthermore, BRG1 is required for the proper localization of SCML2 and its associated deubiquitinase, USP7, to the sex chromosomes during pachynema. SCML2 associated, mono ubiquitination of histone H2A lysine 119 (H2AK119ub1) and acetylation of histone lysine 27 (H3K27ac) are elevated in Brg1cKO testes. Coincidentally, the PRC1 ubiquitin ligase, RNF2 is activated while a histone H2A/H2B deubiquitinase, USP3 is repressed. Thus, BRG1 impacts the male epigenome by influencing the localization and expression of epigenetic modifiers. This mechanism highlights a novel paradigm of co-operativity between SWI/SNF and PRC1.Summary statementBRG1, a catalytic subunit of SWI/SNF chromatin remodeling complex, interacts with SCML2 (Sex comb on midleg-like 2), a polycomb repressive 1 (PRC1) factor, to regulate transcription during spermatogenesis. This represents a novel paradigm of SWI/SNF-PRC1 co-operation during gametogenesis.

INO80 requires a polycomb subunit to regulate the establishment of poised chromatin in murine spermatocytes

Development ◽  
2022 ◽  
Vol 149 (1) ◽  
Author(s):  
Prabuddha Chakraborty ◽  
Terry Magnuson
Keyword(s):  
Chromatin Remodeling ◽  
Binding Sites ◽  
Strand Break ◽  
Rna Seq ◽  
Genome Wide Analysis ◽  
The Core ◽  
Chromatin Remodeling Complex ◽  
Genome Wide ◽  
Dna Double Strand Break ◽  
Transcription Program

ABSTRACT INO80 is the catalytic subunit of the INO80-chromatin remodeling complex that is involved in DNA replication, repair and transcription regulation. Ino80 deficiency in murine spermatocytes (Ino80cKO) results in pachytene arrest of spermatocytes due to incomplete synapsis and aberrant DNA double-strand break repair, which leads to apoptosis. RNA-seq on Ino80cKO spermatocytes revealed major changes in transcription, indicating that an aberrant transcription program arises upon INO80 depletion. In Ino80WT spermatocytes, genome-wide analysis showed that INO80-binding sites were mostly promoter proximal and necessary for the regulation of spermatogenic gene expression, primarily of premeiotic and meiotic genes. Furthermore, most of the genes poised for activity, as well as those genes that are active, shared INO80 binding. In Ino80cKO spermatocytes, most poised genes demonstrated de-repression due to reduced H3K27me3 enrichment and, in turn, showed increased expression levels. INO80 interacts with the core PRC2 complex member SUZ12 and promotes its recruitment. Furthermore, INO80 mediates H2A.Z incorporation at the poised promoters, which was reduced in Ino80cKO spermatocytes. Taken together, INO80 is emerging as a major regulator of the meiotic transcription program by mediating poised chromatin establishment through SUZ12 binding.

scholarly journals The ACF Chromatin Remodeling Complex is Essential for Polycomb Repression

2021 ◽  
Author(s):  
Eric U Selker ◽  
Elizabeth T. Wiles ◽  
Colleen C. Mumford ◽  
Kevin J. McNaught ◽  
Hideki Tanizawa
Keyword(s):  
Chromatin Remodeling ◽  
Chromatin Modification ◽  
Gene Repression ◽  
Facultative Heterochromatin ◽  
Direct Role ◽  
H3k27 Methylation ◽  
Chromatin Remodeling Complex ◽  
Polycomb Repression ◽  
Health And Development ◽  
Multicellular Organisms

Establishing and maintaining appropriate gene repression is critical for the health and development of multicellular organisms. Histone H3 lysine 27 (H3K27) methylation is a chromatin modification associated with repressed facultative heterochromatin, but the mechanism of this repression remains unclear. We used a forward genetic approach to identify genes involved in transcriptional silencing of H3K27-methylated chromatin in the filamentous fungus Neurospora crassa. We found that the N. crassa homologs of ISWI (NCU03875) and ACF (NCU00164) are required for repression of a subset of H3K27-methylated genes and that they form an ACF chromatin remodeling complex. This N. crassa ACF complex interacts with chromatin throughout the genome, yet association with facultative heterochromatin is specifically promoted by the H3K27 methyltransferase, SET-7. H3K27-methylated genes that are upregulated when iswi or acf1 are deleted show a downstream shift of the +1 nucleosome, suggesting that proper nucleosome positioning is critical for repression of facultative heterochromatin. Our findings support a direct role for the ACF complex in Polycomb repression.

scholarly journals A specialized condensin complex participates in somatic nuclear maturation in Tetrahymena thermophila

2019 ◽  
Vol 30 (11) ◽  
pp. 1326-1338 ◽  
Author(s):  
Rachel Howard-Till ◽  
Miao Tian ◽  
Josef Loidl
Keyword(s):  
Sexual Reproduction ◽  
Chromatin Remodeling ◽  
Nuclear Division ◽  
Tetrahymena Thermophila ◽  
Vegetative Cells ◽  
Nuclear Maturation ◽  
The Core ◽  
Condensin Complex ◽  
Chromatin Remodeling Complex ◽  
Putative Member

Condensins are highly conserved proteins that are important for chromosome maintenance in nearly all forms of life. Although many organisms employ two forms of the condensin complex, the condensin genes in Tetrahymena have expanded even further. Here we report a form of condensin that is specifically active during sexual reproduction. This complex, condensin D, is composed of the core condensin proteins, Smc2 and Smc4, and two unique subunits, the kleisin Cph5 and Cpd2. Cpd2 is also found in somatic nuclei in vegetative cells, but is dispensable for growth and nuclear division. Immunoprecipitation experiments show that condensin D interacts with a putative member of a chromatin-remodeling complex during development. Condensin D is required for sexual reproduction and for endoreplication and genome reduction of the progeny’s somatic nuclei. Altogether, Tetrahymena possesses at least four forms of condensin to fulfill the needs of maintaining chromosomes in two different nuclei containing the somatic and germline genomes.

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