scholarly journals Detailed profiles of histone modification in male germ line cells of the young and aged mice

2019 ◽  
Author(s):  
Misako Tatehana ◽  
Ryuichi Kimura ◽  
Kentaro Mochizuki ◽  
Noriko Osumi
Keyword(s):  
Gene Expression ◽  
Histone Modification ◽  
Histone Modifications ◽  
Sex Chromosomes ◽  
De Novo ◽  
Germ Line ◽  
Epidemiological Studies ◽  
De Novo Mutations ◽  
Male Germ Line ◽  
M Phase

Human epidemiological studies have shown paternal aging as one of the risks for neurodevelopmental disorders such as autism in offspring. A recent study has suggested that factors other than de novo mutations due to aging can influence biology of offspring. Here we are focusing on epigenetic alterations in sperm that can influence offspring developmental programs. In this study, we qualitatively and semi-quantitatively evaluated histone modification patterns in male germ line cells throughout spermatogenesis based on immunostaining of testes taken from young (3 months) and aged (12 months) old mice. Although localization patterns were not obviously changed between young and aged testes, some histone modification showed differences in their intensity. Among histone modifications that repress gene expression, H3K9me3 was decreased in the male germ line cells in the aged testis, while H3K27me2/3 was increased. The intensity of H3K27ac, an active mark, was relatively low in the aged testis. Interestingly, H3K27ac was detected in putative sex chromosomes of round spermatids, while other chromosomes were occupied by a repressive mark H3K27me3. Among other histone modifications that activate gene expression, H3K4me2 was drastically decreased in the male germ line cells in the aged testis. H3K79me3 was contrastingly increased and accumulated on the sex chromosomes at M-phase spermatocytes. Therefore, aging induced alterations in the amount of histone modifications, of which patterns were different in individual histone modifications. Moreover, histone modification seems to be differentially regulated by aging on the sex chromosomes and on others. These findings would help elucidate epigenetic mechanisms underlying influence of paternal aging on offspring's development.

scholarly journals De Novo DNA Methylation in the Male Germ Line Occurs by Default but Is Excluded at Sites of H3K4 Methylation

Cell Reports ◽  
2013 ◽  
Vol 4 (1) ◽  
pp. 205-219 ◽  
Author(s):  
Purnima Singh ◽  
Arthur X. Li ◽  
Diana A. Tran ◽  
Nathan Oates ◽  
Eun-Rim Kang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Germ Line ◽  
H3k4 Methylation ◽  
Male Germ Line

scholarly journals Dynamics of gene expression with positive feedback to histone modifications at bivalent domains

2018 ◽  
Vol 32 (07) ◽  
pp. 1850075
Author(s):  
Rongsheng Huang ◽  
Jinzhi Lei
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Histone Modification ◽  
Histone Modifications ◽  
Positive Feedback ◽  
State Transition ◽  
Embryonic Stem ◽  
Cell Cycles ◽  
Histone Marks

Experiments have shown that in embryonic stem cells, the promoters of many lineage-control genes contain “bivalent domains”, within which the nucleosomes possess both active (H3K4me3) and repressive (H3K27me3) marks. Such bivalent modifications play important roles in maintaining pluripotency in embryonic stem cells. Here, to investigate gene expression dynamics when there are regulations in bivalent histone modifications and random partition in cell divisions, we study how positive feedback to histone methylation/demethylation controls the transition dynamics of the histone modification patterns along with cell cycles. We constructed a computational model that includes dynamics of histone marks, three-stage chromatin state transitions, transcription and translation, feedbacks from protein product to enzymes to regulate the addition and removal of histone marks, and the inheritance of nucleosome state between cell cycles. The model reveals how dynamics of both nucleosome state transition and gene expression are dependent on the enzyme activities and feedback regulations. Results show that the combination of stochastic histone modification at each cell division and the deterministic feedback regulation work together to adjust the dynamics of chromatin state transition in stem cell regenerations.

Changes in DNA methylation during mouse embryonic development in relation to X-chromosome activity and imprinting

1990 ◽  
Vol 326 (1235) ◽  
pp. 299-312 ◽  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Embryonic Development ◽  
X Chromosome ◽  
De Novo ◽  
Germ Line ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Chromatin Configuration ◽  
Methylation Patterns

Changing DNA methylation patterns during embryonic development are discussed in relation to differential gene expression, changes in X-chromosome activity and genomic imprinting. Sperm DNA is more methylated than oocyte DNA, both overall and for specific sequences. The methylation difference between the gametes could be one of the mechanisms (along with chromatin structure) regulating initial differences in expression of parental alleles in early development. There is a loss of methylation during development from the morula to the blastocyst and a marked decrease in methylase activity. De novo methylation becomes apparent around the time of implantation and occurs to a lesser extent in extra-embryonic tissue DNA. In embryonic DNA, de novo methylation begins at the time of random X-chromosome inactivation but it continues to occur after X-chromosome inactivation and may be a mechanism that irreversibly fixes specific patterns of gene expression and X-chromosome inactivity in the female. The germ line is probably delineated before extensive de novo methylation and hence escapes this process. The marked undermethylation of the germ line DNA may be a prerequisite for X-chromosome reactivation. The process underlying reactivation and removal of parent-specific patterns of gene expression may be changes in chromatin configuration associated with meiosis and a general reprogramming of the germ line to developmental totipotency.

scholarly journals Noncoding de novo mutations contribute to autism spectrum disorder via chromatin interactions

2019 ◽  
Author(s):  
Il Bin Kim ◽  
Taeyeop Lee ◽  
Junehawk Lee ◽  
Jonghun Kim ◽  
Hyunseong Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Autism Spectrum Disorder ◽  
Stem Cells ◽  
Target Genes ◽  
De Novo ◽  
Regulatory Elements ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutations ◽  
Chromatin Interactions

Three-dimensional chromatin structures regulate gene expression across genome. The significance of de novo mutations (DNMs) affecting chromatin interactions in autism spectrum disorder (ASD) remains poorly understood. We generated 931 whole-genome sequences for Korean simplex families to detect DNMs and identified target genes dysregulated by noncoding DNMs via long-range chromatin interactions between regulatory elements. Notably, noncoding DNMs that affect chromatin interactions exhibited transcriptional dysregulation implicated in ASD risks. Correspondingly, target genes were significantly involved in histone modification, prenatal brain development, and pregnancy. Both noncoding and coding DNMs collectively contributed to low IQ in ASD. Indeed, noncoding DNMs resulted in alterations, via chromatin interactions, in target gene expression in primitive neural stem cells derived from human induced pluripotent stem cells from an ASD subject. The emerging neurodevelopmental genes, not previously implicated in ASD, include CTNNA2, GRB10, IKZF1, PDE3B, and BACE1. Our results were reproducible in 517 probands from MSSNG cohort. This work demonstrates that noncoding DNMs contribute to ASD via chromatin interactions.

scholarly journals Histone modifications centric-regulation in osteogenic differentiation

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Kun Li ◽  
Jinxiang Han ◽  
Ziqiang Wang
Keyword(s):  
Gene Expression ◽  
Histone Modification ◽  
Osteogenic Differentiation ◽  
Histone Modifications ◽  
Marker Genes ◽  
Gene Promoters ◽  
Control Of Gene Expression ◽  
Osteogenic Gene Expression ◽  
Checkpoint Genes

AbstractHistone modification critically contributes to the epigenetic control of gene expression by changing the configuration of chromatin and modifying the access of transcription factors to gene promoters. Recently, we observed that histone acetylation and crotonylation mediated the expression of endocytosis-related genes and tumor-related immune checkpoint genes by regulating the enrichment of signal transducer and activator of transcription 3 on these gene promoters in Alzheimer’s disease and tumorigenesis, suggesting that histone modification plays an important role in disease development. Furthermore, studies performed in the past decade revealed that histone modifications affect osteogenic differentiation by regulating the expression of osteogenic marker genes. In this review, we summarize and discuss the histone modification-centric regulation of osteogenic gene expression. This review improves the understanding of the role of histone modifications in osteogenic differentiation and describes its potential as a therapeutic target for osteogenic differentiation-related diseases.

scholarly journals KRAB-Induced Heterochromatin Effectively Silences PLOD2 Gene Expression in Somatic Cells and Is Resilient to TGFβ1 Activation

2020 ◽  
Vol 21 (10) ◽  
pp. 3634
Author(s):  
Rutger A. F. Gjaltema ◽  
Désirée Goubert ◽  
Christian Huisman ◽  
Consuelo del Pilar García Tobilla ◽  
Mihály Koncz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Histone Modifications ◽  
Mammalian Cells ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Context Dependency ◽  
Dependent Manner ◽  
In Vivo Models ◽  
Epigenetic Editing

Epigenetic editing, an emerging technique used for the modulation of gene expression in mammalian cells, is a promising strategy to correct disease-related gene expression. Although epigenetic reprogramming results in sustained transcriptional modulation in several in vivo models, further studies are needed to develop this approach into a straightforward technology for effective and specific interventions. Important goals of current research efforts are understanding the context-dependency of successful epigenetic editing and finding the most effective epigenetic effector(s) for specific tasks. Here we tested whether the fibrosis- and cancer-associated PLOD2 gene can be repressed by the DNA methyltransferase M.SssI, or by the non-catalytic Krüppel associated box (KRAB) repressor directed to the PLOD2 promoter via zinc finger- or CRISPR-dCas9-mediated targeting. M.SssI fusions induced de novo DNA methylation, changed histone modifications in a context-dependent manner, and led to 50%–70% reduction in PLOD2 expression in fibrotic fibroblasts and in MDA-MB-231 cancer cells. Targeting KRAB to PLOD2 resulted in the deposition of repressive histone modifications without DNA methylation and in almost complete PLOD2 silencing. Interestingly, both long-term TGFβ1-induced, as well as unstimulated PLOD2 expression, was completely repressed by KRAB, while M.SssI only prevented the TGFβ1-induced PLOD2 expression. Targeting transiently expressed dCas9-KRAB resulted in sustained PLOD2 repression in HEK293T and MCF-7 cells. Together, these findings point to KRAB outperforming DNA methylation as a small potent targeting epigenetic effector for silencing TGFβ1-induced and uninduced PLOD2 expression.

Germ line origins of de novo mutations in hemophilia B families

1994 ◽  
Vol 94 (3) ◽  
Author(s):  
ArthurR. Thompson ◽  
Shi-Han Chen
Keyword(s):  
De Novo ◽  
Germ Line ◽  
Hemophilia B ◽  
De Novo Mutations

scholarly journals Promoter-Dependent Mechanism Leading to Selective Hypomethylation within the 5′ Region of Gene MAGE-A1 in Tumor Cells

2004 ◽  
Vol 24 (11) ◽  
pp. 4781-4790 ◽  
Author(s):  
Charles De Smet ◽  
Axelle Loriot ◽  
Thierry Boon
Keyword(s):  
Tumor Cells ◽  
De Novo ◽  
Germ Line ◽  
Male Germ Line ◽  
Site Specific ◽  
Local Inhibition ◽  
Genome Wide ◽  
Somatic Tissues ◽  
Dependent Mechanism

ABSTRACT Several male germ line-specific genes, including MAGE-A1, rely on DNA methylation for their repression in normal somatic tissues. These genes become activated in many types of tumors in the course of the genome-wide demethylation process which often accompanies tumorigenesis. We show that in tumor cells expressing MAGE-A1, the 5′ region is significantly less methylated than the other parts of the gene. The process leading to this site-specific hypomethylation does not appear to be permanent in these tumor cells, since in vitro-methylated MAGE-A1 sequences do not undergo demethylation after being stably transfected. However, in these cells there is a process that inhibits de novo methylation within the 5′ region of MAGE-A1, since unmethylated MAGE-A1 transgenes undergo remethylation at all CpGs except those located within the 5′ region. This local inhibition of methylation appears to depend on promoter activity. We conclude that the site-specific hypomethylation of MAGE-A1 in tumor cells relies on a transient process of demethylation followed by a persistent local inhibition of remethylation due to the presence of transcription factors.

scholarly journals Environmental Exposure of the Mouse Germ Line: DNA Adducts in Spermatozoa and Formation of De Novo Mutations during Spermatogenesis

PLoS ONE ◽  
2010 ◽  
Vol 5 (6) ◽  
pp. e11349 ◽  
Author(s):  
Ann-Karin Olsen ◽  
Åshild Andreassen ◽  
Rajinder Singh ◽  
Richard Wiger ◽  
Nur Duale ◽  
...  
Keyword(s):  
Environmental Exposure ◽  
Dna Adducts ◽  
De Novo ◽  
Germ Line ◽  
De Novo Mutations

scholarly journals Regulation of ALF Gene Expression in Somatic and Male Germ Line Tissues Involves Partial and Site-specific Patterns of Methylation

2002 ◽  
Vol 277 (20) ◽  
pp. 17765-17774 ◽  
Author(s):  
Wensheng Xie ◽  
SangYoon Han ◽  
Mohammed Khan ◽  
Jeff DeJong
Keyword(s):  
Gene Expression ◽  
Germ Line ◽  
Male Germ Line ◽  
Site Specific
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