scholarly journals Oocyte-specific deletion of Hdac8 in mice reveals stage-specific effects on fertility

Reproduction ◽  
2019 ◽  
Vol 157 (3) ◽  
pp. 305-316 ◽  
Author(s):  
Vijay Pratap Singh ◽  
Wei-Ting Yueh ◽  
Jennifer L Gerton ◽  
Francesca E Duncan
Keyword(s):  
Chromosome Segregation ◽  
Histone Deacetylases ◽  
Reproductive Function ◽  
S Phase ◽  
Female Fertility ◽  
Specific Expression ◽  
Specific Effects ◽  
Chromatid Cohesion ◽  
Class 1 ◽  
Specific Deletion

Eighteen histone deacetylases exist in mammals. The class 1 histone deacetylases HDAC1 and HDAC2 are important for oogenesis and fertility in mice, likely via their effects on histones. The reproductive function of HDAC8, another class 1 enzyme, has not been explored. One key target of HDAC8 is the SMC3 subunit of cohesin, an essential complex mediating sister chromatid cohesion and chromosome segregation. In current models, HDAC8 activity is required for SMC3 recycling, but this function should be dispensable in oocytes since cohesion is established during pre-meiotic S phase and maintained until meiotic resumption during ovulation. Whether other oocyte-specific HDAC8-mediated deacetylation events are required for oogenesis and female fertility is unknown. We used two Cre drivers to remove Hdac8 at specific stages of oocyte development to address whether HDAC8 is required for female fertility in mice. When HDAC8 was knocked out in oocytes in primary and later stage follicles (Zp3-Cre), oogenesis and folliculogenesis appeared normal and mice were fertile. However, females were subfertile when HDAC8 was knocked out prior to pre-meiotic S phase and cohesion establishment (Vasa-Cre). This subfertility was independent of chromosome segregation errors during meiosis but rather appeared to be the result of defects in oogenesis that resulted in smaller fully grown oocytes with a reduced ability to resume meiosis. In all cases, we did not observe compensatory changes in HDAC1, HDAC2 and HDAC3 levels. Thus, although oocyte-specific expression of HDAC8 is not essential for mouse oogenesis after meiotic S phase, it contributes to optimal fertility. We infer that oocyte-specific expression of the deacetylase HDAC8 is required early in oogenesis for optimal fertility.

scholarly journals The yeast S phase checkpoint enables replicating chromosomes to bi-orient and restrain spindle extension during S phase distress

2005 ◽  
Vol 168 (7) ◽  
pp. 999-1012 ◽  
Author(s):  
Jeff Bachant ◽  
Shannon R. Jessen ◽  
Sarah E. Kavanaugh ◽  
Candida S. Fielding
Keyword(s):  
Dna Replication ◽  
Chromosome Segregation ◽  
Replication Fork ◽  
S Phase ◽  
Origin Of Replication ◽  
Independent Manner ◽  
Checkpoint Signaling ◽  
Hydroxyurea Treatment ◽  
Chromatid Cohesion ◽  
S Phase Checkpoint

The budding yeast S phase checkpoint responds to hydroxyurea-induced nucleotide depletion by preventing replication fork collapse and the segregation of unreplicated chromosomes. Although the block to chromosome segregation has been thought to occur by inhibiting anaphase, we show checkpoint-defective rad53 mutants undergo cycles of spindle extension and collapse after hydroxyurea treatment that are distinct from anaphase cells. Furthermore, chromatid cohesion, whose dissolution triggers anaphase, is dispensable for S phase checkpoint arrest. Kinetochore–spindle attachments are required to prevent spindle extension during replication blocks, and chromosomes with two centromeres or an origin of replication juxtaposed to a centromere rescue the rad53 checkpoint defect. These observations suggest that checkpoint signaling is required to generate an inward force involved in maintaining preanaphase spindle integrity during DNA replication distress. We propose that by promoting replication fork integrity under these conditions Rad53 ensures centromere duplication. Replicating chromosomes can then bi-orient in a cohesin-independent manner to restrain untimely spindle extension.

scholarly journals A novel mechanism for the establishment of sister chromatid cohesion by the ECO1 acetyltransferase

2015 ◽  
Vol 26 (1) ◽  
pp. 117-133 ◽  
Author(s):  
Vincent Guacci ◽  
Jeremiah Stricklin ◽  
Michelle S. Bloom ◽  
Xuánzōng Guō ◽  
Meghna Bhatter ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Current Model ◽  
S Phase ◽  
High Fidelity ◽  
In Vivo Assays ◽  
Sister Chromatids ◽  
Chromatid Cohesion ◽  
Cohesin Subunit ◽  
Mutant Cells

Cohesin complex mediates cohesion between sister chromatids, which promotes high-fidelity chromosome segregation. Eco1p acetylates the cohesin subunit Smc3p during S phase to establish cohesion. The current model posits that this Eco1p-mediated acetylation promotes establishment by abrogating the ability of Wpl1p to destabilize cohesin binding to chromosomes. Here we present data from budding yeast that is incompatible with this Wpl1p-centric model. Two independent in vivo assays show that a wpl1∆ fails to suppress cohesion defects of eco1∆ cells. Moreover, a wpl1∆ also fails to suppress cohesion defects engendered by blocking just the essential Eco1p acetylation sites on Smc3p (K112, K113). Thus removing WPL1 inhibition is insufficient for generating cohesion without ECO1 activity. To elucidate how ECO1 promotes cohesion, we conducted a genetic screen and identified a cohesion activator mutation in the SMC3 head domain (D1189H). Smc3-D1189H partially restores cohesion in eco1∆ wpl1∆ or eco1 mutant cells but robustly restores cohesion in cells blocked for Smc3p K112 K113 acetylation. These data support two important conclusions. First, acetylation of the K112 K113 region by Eco1p promotes cohesion establishment by altering Smc3p head function independent of its ability to antagonize Wpl1p. Second, Eco1p targets other than Smc3p K112 K113 are necessary for efficient establishment.

scholarly journals Cohesion is established during DNA replication utilising chromosome associated cohesin rings as well as those loaded de novo onto nascent DNAs

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Madhusudhan Srinivasan ◽  
Marco Fumasoni ◽  
Naomi J Petela ◽  
Andrew Murray ◽  
Kim A Nasmyth
Keyword(s):  
Dna Replication ◽  
Chromosome Segregation ◽  
Mitotic Chromosome ◽  
De Novo ◽  
S Phase ◽  
Eukaryotic Cells ◽  
Replication Forks ◽  
Chromatid Cohesion ◽  
Different Types ◽  
Associated Proteins

Sister chromatid cohesion essential for mitotic chromosome segregation is thought to involve the co-entrapment of sister DNAs within cohesin rings. Although cohesin can load onto chromosomes throughout the cell cycle, it only builds cohesion during S phase. A key question is whether cohesion is generated by conversion of cohesin complexes associated with un-replicated DNAs ahead of replication forks into cohesive structures behind them, or from nucleoplasmic cohesin that is loaded de novo onto nascent DNAs associated with forks, a process that would be dependent on cohesin’s Scc2 subunit. We show here that in S. cerevisiae, both mechanisms exist and that each requires a different set of replisome-associated proteins. Cohesion produced by cohesin conversion requires Tof1/Csm3, Ctf4 and Chl1 but not Scc2 while that created by Scc2-dependent de novo loading at replication forks requires the Ctf18-RFC complex. The association of specific replisome proteins with different types of cohesion establishment opens the way to a mechanistic understanding of an aspect of DNA replication unique to eukaryotic cells.

scholarly journals Evidence for cohesin sliding along budding yeast chromosomes

Open Biology ◽  
2016 ◽  
Vol 6 (6) ◽  
pp. 150178 ◽  
Author(s):  
Maria Ocampo-Hafalla ◽  
Sofía Muñoz ◽  
Catarina P. Samora ◽  
Frank Uhlmann
Keyword(s):  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Budding Yeast ◽  
Transcription Termination ◽  
Gene Activation ◽  
S Phase ◽  
Cohesin Complex ◽  
Sister Chromatids ◽  
Chromatid Cohesion ◽  
Active Genes

The ring-shaped cohesin complex is thought to topologically hold sister chromatids together from their synthesis in S phase until chromosome segregation in mitosis. How cohesin stably binds to chromosomes for extended periods, without impeding other chromosomal processes that also require access to the DNA, is poorly understood. Budding yeast cohesin is loaded onto DNA by the Scc2–Scc4 cohesin loader at centromeres and promoters of active genes, from where cohesin translocates to more permanent places of residence at transcription termination sites. Here we show that, at the GAL2 and MET17 loci, pre-existing cohesin is pushed downstream along the DNA in response to transcriptional gene activation, apparently without need for intermittent dissociation or reloading. We observe translocation intermediates and find that the distribution of most chromosomal cohesin is shaped by transcription. Our observations support a model in which cohesin is able to slide laterally along chromosomes while maintaining topological contact with DNA. In this way, stable cohesin binding to DNA and enduring sister chromatid cohesion become compatible with simultaneous underlying chromosomal activities, including but maybe not limited to transcription.

scholarly journals Multiple Subunits of the Caenorhabditis elegans Anaphase-Promoting Complex Are Required for Chromosome Segregation During Meiosis I

Genetics ◽  
2002 ◽  
Vol 160 (2) ◽  
pp. 805-813 ◽  
Author(s):  
Edward S Davis ◽  
Lucia Wille ◽  
Barry A Chestnut ◽  
Penny L Sadler ◽  
Diane C Shakes ◽  
...  
Keyword(s):  
Rna Interference ◽  
Caenorhabditis Elegans ◽  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Sister Chromatid Cohesion ◽  
Anaphase Promoting Complex ◽  
Genetic Screens ◽  
Chromatid Cohesion ◽  
Interference Studies ◽  
Meiosis I

Abstract Two genes, originally identified in genetic screens for Caenorhabditis elegans mutants that arrest in metaphase of meiosis I, prove to encode subunits of the anaphase-promoting complex or cyclosome (APC/C). RNA interference studies reveal that these and other APC/C subunits are essential for the segregation of chromosomal homologs during meiosis I. Further, chromosome segregation during meiosis I requires APC/C functions in addition to the release of sister chromatid cohesion.

scholarly journals Double or nothing: a Drosophila mutation affecting meiotic chromosome segregation in both females and males.

Genetics ◽  
1994 ◽  
Vol 136 (3) ◽  
pp. 953-964 ◽  
Author(s):  
D P Moore ◽  
W Y Miyazaki ◽  
J E Tomkiel ◽  
T L Orr-Weaver
Keyword(s):  
Cell Death ◽  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Meiotic Chromosome ◽  
Sister Chromatid Cohesion ◽  
Aberrant Chromosome ◽  
Chromatid Cohesion ◽  
Meiotic Nondisjunction ◽  
Lethal Allele ◽  
Meiosis I

Abstract We describe a Drosophila mutation, Double or nothing (Dub), that causes meiotic nondisjunction in a conditional, dominant manner. Previously isolated mutations in Drosophila specifically affect meiosis either in females or males, with the exception of the mei-S332 and ord genes which are required for proper sister-chromatid cohesion. Dub is unusual in that it causes aberrant chromosome segregation almost exclusively in meiosis I in both sexes. In Dub mutant females both nonexchange and exchange chromosomes undergo nondisjunction, but the effect of Dub on nonexchange chromosomes is more pronounced. Dub reduces recombination levels slightly. Multiple nondisjoined chromosomes frequently cosegregate to the same pole. Dub results in nondisjunction of all chromosomes in meiosis I of males, although the levels are lower than in females. When homozygous, Dub is a conditional lethal allele and exhibits phenotypes consistent with cell death.

scholarly journals Identification of a novel nucleolar protein complex required for mitotic chromosome segregation through centromeric accumulation of Aurora B

2020 ◽  
Vol 48 (12) ◽  
pp. 6583-6596
Author(s):  
Akiko Fujimura ◽  
Yuki Hayashi ◽  
Kazashi Kato ◽  
Yuichiro Kogure ◽  
Mutsuro Kameyama ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Protein Complex ◽  
Metaphase Plate ◽  
Nucleolar Protein ◽  
Aurora B ◽  
Mitotic Progression ◽  
Mitotic Chromosomes ◽  
Nucleolar Proteins ◽  
Chromatid Cohesion ◽  
Wd Repeat

Abstract The nucleolus is a membrane-less nuclear structure that disassembles when cells undergo mitosis. During mitosis, nucleolar factors are thus released from the nucleolus and dynamically change their subcellular localization; however, their functions remain largely uncharacterised. Here, we found that a nucleolar factor called nucleolar protein 11 (NOL11) forms a protein complex with two tryptophan-aspartic acid (WD) repeat proteins named WD-repeat protein 43 (WDR43) and Cirhin in mitotic cells. This complex, referred to here as the NWC (NOL11-WDR43-Cirhin) complex, exists in nucleoli during interphase and translocates to the periphery of mitotic chromosomes, i.e., perichromosomal regions. During mitotic progression, both the congression of chromosomes to the metaphase plate and sister chromatid cohesion are impaired in the absence of the NWC complex, as it is required for the centromeric enrichment of Aurora B and the associating phosphorylation of histone H3 at threonine 3. These results reveal the characteristics of a novel protein complex consisting of nucleolar proteins, which is required for regulating kinetochores and centromeres to ensure faithful chromosome segregation.

scholarly journals Distinct Mechanisms Involving Diverse Histone Deacetylases Repress Expression of the Two Gonadotropin β-Subunit Genes in Immature Gonadotropes, and Their Actions Are Overcome by Gonadotropin-Releasing Hormone

2007 ◽  
Vol 27 (11) ◽  
pp. 4105-4120 ◽  
Author(s):  
Stefan Lim ◽  
Min Luo ◽  
Mingshi Koh ◽  
Meng Yang ◽  
Mohammed Nizam bin Abdul Kadir ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Reproductive Function ◽  
Gonadotropin Releasing Hormone ◽  
Β Subunit ◽  
Releasing Hormone ◽  
Calcium Calmodulin Dependent ◽  
Gnrh Release ◽  
Dependent Protein ◽  
Reproductive Cycles ◽  
Class Iia Hdacs

ABSTRACT The gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are produced in the embryonic pituitary in response to delivery of the hypothalamic gonadotropin releasing hormone (GnRH). GnRH has a pivotal role in reestablishing gonadotropin levels at puberty in primates, and for many species with extended reproductive cycles, these are reinitiated in response to central nervous system-induced GnRH release. Thus, a clear role is evident for GnRH in overcoming repression of these genes. Although the mechanisms through which GnRH actively stimulates LH and FSH β-subunit (FSHβ) gene transcription have been described in some detail, there is currently no information on how GnRH overcomes repression in order to terminate reproductively inactive stages. We show here that GnRH overcomes histone deacetylase (HDAC)-mediated repression of the gonadotropin β-subunit genes in immature gonadotropes. The repressive factors associated with each of these genes comprise distinct sets of HDACs and corepressors which allow for differentially regulated derepression of these two genes, produced in the same cell by the same regulatory hormone. We find that GnRH activation of calcium/calmodulin-dependent protein kinase I (CaMKI) plays a crucial role in the derepression of the FSHβ gene involving phosphorylation of several class IIa HDACs associated with both the FSHβ and Nur77 genes, and we propose a model for the mechanisms involved. In contrast, derepression of the LH β-subunit gene is not CaMK dependent. This demonstration of HDAC-mediated repression of these genes could explain the temporal shut-down of reproductive function at certain periods of the life cycle, which can easily be reversed by the actions of the hypothalamic regulatory hormone.

scholarly journals Subfertility in androgen-insensitive female mice is rescued by transgenic FSH

2017 ◽  
Vol 29 (7) ◽  
pp. 1426 ◽  
Author(s):  
K. A. Walters ◽  
M. C. Edwards ◽  
M. Jimenez ◽  
D. J. Handelsman ◽  
C. M. Allan
Keyword(s):  
Androgen Receptor ◽  
Litter Size ◽  
Ovarian Function ◽  
Reproductive Function ◽  
Antral Follicle ◽  
Female Fertility ◽  
Wild Type ◽  
Female Reproduction ◽  
Androgen Insensitivity ◽  
Female Mice

Androgens synergise with FSH in female reproduction but the nature of their interaction in ovarian function and fertility is not clear. In the present study, we investigated this interaction, notably whether higher endogenous FSH can overcome defective androgen actions in androgen receptor (AR)-knockout (ARKO) mice. We generated and investigated the reproductive function of mutant mice exhibiting AR resistance with or without expression of human transgenic FSH (Tg-FSH). On the background of inactivated AR signalling, which alone resulted in irregular oestrous cycles and reduced pups per litter, ovulation rates and antral follicle health, Tg-FSH expression restored follicle health, ovulation rates and litter size to wild-type levels. However, Tg-FSH was only able to partially rectify the abnormal oestrous cycles observed in ARKO females. Hence, elevated endogenous FSH rescued the intraovarian defects, and partially rescued the extraovarian defects due to androgen insensitivity. In addition, the observed increase in litter size in Tg-FSH females was not observed in the presence of AR signalling inactivation. In summary, the findings of the present study reveal that FSH can rescue impaired female fertility and ovarian function due to androgen insensitivity in female ARKO mice by maintaining follicle health and ovulation rates, and thereby optimal female fertility.

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