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Transcriptional Profiling of CENPA-Depleted Prostate Cancer Cell Lines

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: GSE127836 | GEO | 2019/03/06

REPOSITORIES: GEO

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Functional Taxonomy of CENPA-Bound Genes in Prostate Cancer

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 | GSE127835 | GEO

CENPA as a reader of m6A-modified centromeric RNA to ensure centromere integrity in cancer cells [RIP-Seq]

Project description:Maintaining centromere integrity is crucial for genome stability and proper chromosome segregation during mitosis. CENPA, a conserved histone H3 variant, is localized at the centromeres and plays an essential role in preserving centromere integrity and function. However, the mechanisms that retain CENPA at centromeres remain an enigma. In this study, we identified CENPA as an m6A reader of centromeric RNA (cenRNA), which is essential for its centromeric localization and function in maintaining centromere stability. We discovered a higher level of m6A modification on cenRNA in cancerous cells compared to normal cells. CENPA preferentially binds the cenRNAs with m6A modification, which stabilizes its localization in centromeric regions during the S phase of the cell cycle. We then identified two residues in CENPA responsible for m6A recognition. Mutations in these CENPA residues or removal of m6A on cenRNAs leads to the loss of centromere-bound CENPA during the S phase, thereby resulting in abnormal chromosome separation during mitosis and increased genomic instability. Consequently, this impairment in centromere integrity hindered cancer cell proliferation and tumor growth. Our findings unveiled a novel m6A reading mechanism by CENPA that epigenetically governs centromere integrity in cancer cells, providing potentially new targets for cancer therapy.

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CENPA as a reader of m6A-modified centromeric RNA to ensure centromere integrity in cancer cells [ChIRP-seq]

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CENPA as a reader of m6A-modified centromeric RNA to ensure centromere integrity in cancer cells [MeRIP-seq]

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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.

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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

Paradiplonema papillatum CENPA-V5 IP

Project description:Transmission of genetic material from one generation to the next is a fundamental feature of all living cells. In eukaryotes, a macromolecular complex called the kinetochore plays crucial roles in this process by providing linkage between chromosomes and spindle microtubules. Little is known about this process in evolutionarily diverse protists. Within the supergroup Discoba, Eeuglenozoans forms a highly diversespeciose group of unicellular flagellates -including kinetoplastids, euglenids, and diplonemids. Kinetoplastids have an unconventional kinetochore system, while euglenids have a canonical onekinetochore system. It remains unclear what kind of kinetochores are present in diplonemids, a group of extremely diverse and abundant marine flagellatesplankton. Here, we employed deep homology detection protocols using profile-versus-profile Hidden Markov Model searches and AlphaFold-based structural comparisons to detect homologies that might have been previously missed. Interestingly, we still could not detect orthologs for most of the kinetoplastid nor canonical kinetochore subunits with few exceptions including a putative centromere-specific histone H3 variant (cenH3/CENP-A), the spindle checkpoint protein Mad2, the chromosomal passenger complex members Aurora and INCENP, and broadly conserved proteins like the CLK kinase and the meiotic synaptonemal complex proteins SYCP2 that function at kinetoplastid kinetochores. We examined the localization of five candidate kinetochore-associated proteins in the model diplonemid, Paradiplonema papillatum. PpCENP-A shows discrete dots in the nucleus, implying that it is likely a kinetochore component. PpMad2, PpCLK, PpSYCP2L1 and INCENP reside in the nucleus, but no clear kinetochore localization was observed. Altogether, these results raise a possibility that diplonemids evolved a hitherto unknown type of kinetochore system.

2024-10-21 | PXD054535 | Pride

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

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