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Functional Taxonomy of CENPA-Bound Genes in Prostate Cancer

ABSTRACT: Overexpression of centromeric proteins has been identified in a number of human malignancies, though their functional and mechanistic contributions to disease progression have not been characterized. CENPA, the centromeric histone H3 variant, is the epigenetic mark that determines centromere identity. Here, we demonstrate that CENPA is highly overexpressed in prostate cancer in both tissue and cell lines, and the level of CENPA expression correlates with the stage of disease. Gain-of- and loss-of-function experimentation confirms that CENPA promotes prostate cancer cell line growth. Integrated sequencing studies further reveal a previously unidentified function of CENPA as a transcriptional regulator that modulates expression of critical proliferation, cell-cycle, and centromere/kinetochore genes. Our findings, therefore, suggest a previously undescribed biological function for CENPA, a protein normally thought to be solely and importantly involved in centromere identity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE127835 | GEO | 2019/03/06

REPOSITORIES: GEO

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Transcriptional Profiling of CENPA-Depleted Prostate Cancer Cell Lines

Project description:Overexpression of centromeric proteins has been identified in a number of human malignancies, though their functional and mechanistic contributions to disease progression have not been characterized. CENPA, the centromeric histone H3 variant, is the epigenetic mark that determines centromere identity. Here, we demonstrate that CENPA is highly overexpressed in prostate cancer in both tissue and cell lines, and the level of CENPA expression correlates with the stage of disease. Gain-of- and loss-of-function experimentation confirms that CENPA promotes prostate cancer cell line growth. Integrated sequencing studies further reveal a previously unidentified function of CENPA as a transcriptional regulator that modulates expression of critical proliferation, cell-cycle, and centromere/kinetochore genes. Our findings, therefore, suggest a previously undescribed biological function for CENPA, a protein normally thought to be solely and importantly involved in centromere identity.

2019-03-06 | GSE127836 | GEO

Functional Taxonomy of CENPA-Bound Genes in Prostate Cancer

Project description:Functional Taxonomy of CENPA-Bound Genes in Prostate Cancer

| PRJNA525634 | ENA

Genome-wide maps of heterochromatin state (H3K9me2) in kinetochore and other centromere related mutants.

Project description:We report the high-throughput profiling of histone modification (H3K9me2) in fission yeast Schizosaccharomyces pombe. By obtaining 1-10 ng immunoprecipitated DNA, we generated genome-wide H3K9me2 maps of fission yeast mutants with either deletions of non-essential kinetochore genes or conditional inactivation (temperature sensitive, ts) mutations in essential ones. We find that the impairment of the kinetochore componnets cause various levels (from no to prominent) of heterochroamatin spreading into centromeric core regions. Hence, we conclude that the integrity of the inner kinetochore is required to maintain normal centromeric chromatin organization as well as distinct centromere identity.

2019-09-28 | GSE117948 | GEO

Fission yeasts CENPA and H3K9me Chip-seq

Project description:Centromeres are the regions of eukaryotic chromosomes where kinetochores are assembled and direct the correct segregation of chromosomes. Active centromeres are defined by presence of nucleosomes containing CENP-A, a histone H3 variant, which alone is sufficient to direct kinetochore assembly. Once assembled at a location CENP-A chromatin and the kinetochore is maintained at that location though a positive feedback loop where kinetochore proteins recruited by CENP-A promote deposition of new CENP-A following replication. Although CENP-A chromatin itself is a heritable entity, it is normally associated with specific sequences such as human alpha satellite arrays. Such analyses suggest that properties of centromeric DNA itself may favour assembly of CENP-A rather than H3 nucleosomes. To investigate the innate properties of centromeric DNA we have examined histone dynamics on this DNA assembled in CENP-A chromatin at endogenous centromeres and when assembled only in H3 chromatin at an ectopic location. We demonstrate that H3 occupancy on centromeric DNA is innately low while H3 turnover is high. Moreover, even at an ectopic location centromeric DNA programs H3 deposition in S phase and its eviction during G2 when CENP-A is otherwise deposited. G2 accumulation of RNAPII on centromeric DNA during G2 is consistent with transcription-coupled destabilisation of H3 nucleosomes to favour CENP-A deposition.

2019-03-04 | GSE112454 | GEO

Chromatin immunoprecipitation of centromeric protein CenpA from a human cell line containing a neocentromere in band 13q33.1

Project description:Chromatin Immunoprecipitation of Centromeric Protein CenpA from BBB a human cell line containing a neocentromere in band 13q33.1

2022-11-23 | E-TABM-294 | biostudies-arrayexpress

Chromatin immunoprecipitation of centromeric proteins CenpA and CenpC from human cell lines containing a neocentromere in band 13q21

Project description:Chromatin Immunoprecipitation of Centromeric Proteins, CenpA or CenpC, from human cell lines containing a neocentromere in band 13q21

2006-11-06 | E-TABM-168 | biostudies-arrayexpress

CENPA-Bound Genes and Transcriptional Profiling of CENPA-Depleted Prostate Cancer Cells

Project description:CENPA-Bound Genes and Transcriptional Profiling of CENPA-Depleted Prostate Cancer Cells

| PRJNA525618 | ENA

Mediator promotes CENP-A incorporation at fission yeast centromeres [ChIP-seq]

Project description:At Schizosaccharomyces pombe centromeres, heterochromatin formation is required for de novo incorporation of the histone H3 variant CENP-A/Cnp1, which in turn directs kinetochore assembly and ultimately chromosome segregation during mitosis. Noncoding RNAs (ncRNAs) transcribed by RNA polymerase II (Pol II) directs heterochromatin formation via the RNAi machinery, but also through RNAiindependent RNA processing factors. Control of centromeric ncRNA transcription is therefore a key factor for proper centromere function. We here use transcriptional profiling, gene inactivation experiments, and chromatin immunoprecipitation analyses to demonstrate that the Mediator complex directs ncRNA transcription and regulates centromeric heterochromatin formation in fission yeast. Mediator co-localizes with Pol II at centromeres and loss of the Mediator subunit Med20 causes a dramatic increase in pericentromeric transcription and desilencing of the core centromere. As a consequence, heterochromatin formation is impaired both via the RNAi dependent and independent pathways, resulting in loss of CENP-A/Cnp1 from the core centromere, defect kinetochore function, and a severe chromosome segregation defect. Interestingly, the increased centromeric transcription observed in med20Δ appears to directly block CENP-A/Cnp1 incorporation and inhibition of Pol II transcription can suppress the observed phenotypes. Our data thus identify Mediator as a crucial regulator of ncRNA transcription at fission yeast centromeres and add another crucial layer of regulation to centromere function.

2012-11-06 | GSE35524 | GEO

Mediator promotes CENP-A incorporation at fission yeast centromeres [ChIP-seq]

2012-11-06 | E-GEOD-35524 | biostudies-arrayexpress

Epigenetic centromere identity is precisely maintained through DNA replication but is uniquely specified among human cells

Project description:Centromere identity is defined and maintained epigenetically by the presence of the histone variant CENP-A. How centromeric CENP-A position is specified and precisely maintained through DNA replication is not fully understood. The recently released Telomere-to-Telomere (T2T-CHM13) genome assembly containing the first complete human centromere sequences provides a new resource for examining CENP-A position. Mapping CENP-A position in clones of the same cell line to T2T-CHM13 identified highly similar CENP-A position following multiple cell divisions. In contrast, centromeric CENP-A epialleles were evident at several centromeres of different human cell lines, demonstrating the location of CENP-A enrichment and site of kinetochore recruitment varies among human cells. Across the cell cycle, CENP-A molecules deposited in G1 phase are maintained at their precise position through DNA replication. Thus, despite CENP-A dilution during DNA replication, CENP-A is precisely reloaded onto the same sequences within the daughter centromeres, maintaining unique centromere identity among human cells.

2023-01-01 | GSE221541 | GEO

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