Dux cluster duplication ensures full activation of totipotent genes

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(10)

Published: March 6, 2025

Zygotic genome activation (ZGA) confers to the mouse two-cell (2C) embryo a unique transcriptional profile characterized by transient up-regulation of many totipotency-related genes and MERVL retrotransposons. Intriguingly, those are duplicated clustered in during evolution, including Dux cluster, Obox, Zscan4 family members mice. However, contribution biological significance gene duplication events early development remain poorly understood. Here, we focus on master regulator ZGA that is necessary sufficient for induction 2C-like cells embryonic stem (mESCs). By reducing copies from 31 0 or 1 through CRISPR-Cas9 technology, generate Dux-KO (n = 1) mESC lines, respectively. We uncover awakened much lesser extent mESCs compared wild type following global DNA demethylation reprogramming damage, mimicking intrinsic preimplantation development. Together, cluster critically required full transcripts.

Language: Английский

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Molecular Mechanisms of Facultative Heterochromatin Formation: An X-Chromosome Perspective

Annual Review of Biochemistry, Journal Year: 2020, Volume and Issue: 89(1), P. 255 - 282

Published: April 7, 2020

Facultative heterochromatin (fHC) concerns the developmentally regulated heterochromatinization of different regions genome and, in case mammalian X chromosome and imprinted loci, only one allele a homologous pair. The formation fHC participates timely repression genes, by resisting strong trans activators. In this review, we discuss molecular mechanisms underlying establishment maintenance mammals using mouse model. We focus on X-chromosome inactivation (XCI) as paradigm for but also relate it to genomic imprinting homeobox ( Hox) gene cluster repression. A vital role noncoding transcription and/or transcripts emerges general principle triggering XCI canonical imprinting. However, other types are established through an unknown mechanism, independent Hox clusters noncanonical imprinting). extensively polycomb-group repressive complexes (PRCs), which frequently play maintenance.

Language: Английский

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Paternal preconception phthalate exposure alters sperm methylome and embryonic programming

Environment International, Journal Year: 2021, Volume and Issue: 155, P. 106693 - 106693

Published: June 10, 2021

Preconception environmental conditions have been demonstrated to shape sperm epigenetics and subsequently offspring health development. Our previous findings in humans showed that urinary anti-androgenic phthalate metabolites males were associated with altered methylation blastocyst-stage embryo To corroborate this, we examined the effect of preconception exposure di(2-ethylhexyl) (DEHP) on genome-wide DNA gene expression profiles mice. Eight-week old C57BL/6J male mice exposed either a vehicle control, low, or high dose DEHP (2.5 25 mg/kg/weight, respectively) for 67 days (~2 spermatogenic cycles) mated unexposed females. Reduced representation bisulfite sequencing (RRBS) epididymal was performed gastrulation stage embryos collected RRBS transcriptome analyses both embryonic extra-embryonic lineages. Male resulted 704 differentially methylated regions (DMRs; q-value < 0.05; ≥10% change) sperm, 1,716 DMRs embryonic, 3,181 tissue. Of these, 29 overlapped between F1 tissues, half which concordant changes F0 generations. transcriptomes at E7.5 also by including developmental families such as Hox, Gata, Sox. Additionally, ontology expressed genes enrichment multiple processes development, pattern specification morphogenesis. These data indicate spermatogenesis adult may represent sensitive window alters methylome well developing embryo.

Language: Английский

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RNA polymerase pausing, stalling and bypass during transcription of damaged DNA: from molecular basis to functional consequences

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 50(6), P. 3018 - 3041

Published: March 3, 2022

Cellular DNA is continuously transcribed into RNA by multisubunit polymerases (RNAPs). The continuity of transcription can be disrupted lesions that arise from the activities cellular enzymes, reactions with endogenous and exogenous chemicals or irradiation. Here, we review available data on translesion synthesis RNAPs various domains life, define common principles variations in damage sensing RNAP, consider existing controversies field transcription. Depending type lesion, it may correctly bypassed lead to transcriptional mutagenesis, result stalling. Various affect loading templating base active site interfere nucleotide binding incorporation RNA, impair RNAP translocation. Stalled acts as a sensor during transcription-coupled repair. outcome lesion recognition depends interplay between multiple repair factors, which stimulate bypass increase stalling, plays central role maintaining integrity. Unveiling mechanisms systems thus instrumental for understanding molecular pathways underlying gene regulation genome stability.

Language: Английский

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Allele-specific H3K9me3 and DNA methylation co-marked CpG-rich regions serve as potential imprinting control regions in pre-implantation embryo

Nature Cell Biology, Journal Year: 2022, Volume and Issue: 24(5), P. 783 - 792

Published: April 28, 2022

Language: Английский

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