Widespread Transcriptional Scanning in the Testis Modulates Gene Evolution Rates

Xia, Bo; Yan, Yun; Baron, Maayan; Wagner, Florian; Barkley, Dalia; Chiodin, Marta; Kim, Sang Yong; Keefe, David L.; Alukal, Joseph P.; Boeke, Jef D.; Yanai, Itai

doi:10.1016/j.cell.2019.12.015

Cited by 140 publications

(79 citation statements)

References 105 publications

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“…Additionally, in our comparison of the spermatozoal DNA methylome to that of almost 6,000 somatic tissue samples, we showed that gene ontology terms enriched amongst hypermethylated CpG sites in sperm pointed repeatedly to transcriptional regulation. This is an intriguing finding considering that recent research has shown that high overall levels of transcription during spermatogenesis facilitate transcription-coupled DNA repair mechanisms through so-called "transcriptional scanning" [38]. Given that transcriptional regulation is an essential process for all cell-types, it is striking to observe sperm-specific DNA methylation patterns enriched in these processes.…”

Section: Discussionmentioning

confidence: 93%

The DNA methylome of human sperm is distinct from blood with little evidence for tissue-consistent obesity associations

et al. 2020

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Epidemiological research suggests that paternal obesity may increase the risk of fathering small for gestational age offspring. Studies in non-human mammals indicate that such associations could be mediated by DNA methylation changes in spermatozoa that influence offspring development in utero. Human obesity is associated with differential DNA methylation in peripheral blood. It is unclear, however, whether this differential DNA methylation is reflected in spermatozoa. We profiled genome-wide DNA methylation using the Illumina MethylationEPIC array in a cross-sectional study of matched human blood and sperm from lean (discovery n = 47; replication n = 21) and obese (n = 22) males to analyse tissue covariation of DNA methylation, and identify obesity-associated methylomic signatures. We found that DNA methylation signatures of human blood and spermatozoa are highly discordant, and methylation levels are correlated at only a minority of CpG sites (~1%). At the majority of these sites, DNA methylation appears to be influenced by genetic variation. Obesity-associated DNA methylation in blood was not generally reflected in spermatozoa, and obesity was not associated with altered covariation patterns or accelerated epigenetic ageing in the two tissues. However, one cross-tissue obesity-specific hypermethylated site (cg19357369; chr4:2429884; P = 8.95 × 10 −8 ; 2% DNA methylation difference) was identified, warranting replication and further investigation. When compared to a wide range of human somatic tissue samples (n = 5,917), spermatozoa displayed differential DNA methylation across pathways enriched in transcriptional regulation. Overall, human sperm displays a unique DNA methylation profile that is highly discordant to, and practically uncorrelated with, that of matched peripheral blood. We observed that obesity was only nominally associated with differential DNA methylation in PLOS GENETICS

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Section: Discussionmentioning

confidence: 93%

The DNA methylome of human sperm is distinct from blood with little evidence for tissue-consistent obesity associations

et al. 2020

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“…At this stage, damage accumulation is spontaneous while damage dilution via proliferation is not supported in most cell types. During the process of fertilization or before/after it, this damage gets thoroughly checked, cleared and diluted by the transition to the "pro-stemness" state[78][79][80]100 . An example of such a "reset" function exists at fertilization in C. elegans where lysosomal functions in oocytes are enhanced by sperm-secreted hormones, allowing degradation of protein aggregates and protein homeostasis 101.…”

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confidence: 99%

“…Thus, a combination of cell growth, selection, and proliferation dilutes mild damage, in addition to the removal of damage through specialized detoxification, repair, excretion, preemption, and other approaches. These mechanisms together allow the cells to keep the damage in control 80.…”

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confidence: 99%

How can aging be reversed? Exploring rejuvenation from a damage‐based perspective

Zhang

Gladyshev

2020

Advanced Genetics

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Advanced age is associated with accumulation of damage and other deleterious changes and a consequential systemic decline of function. This decline affects all organs and systems in an organism, leading to their inadaptability to the environment, and therefore is thought to be inevitable for humans and most animal species. However, in vitro and in vivo application of reprogramming strategies, which convert somatic cells to induced pluripotent stem cells, has demonstrated that the aged cells can be rejuvenated. Moreover, the data and theoretical considerations suggest that reversing the biological age of somatic cells (from old to young) and de-differentiating somatic cells into stem cells represent two distinct processes that take place during rejuvenation, and thus they may be differently targeted. We advance a stemnessfunction model to explain these data and discuss a possibility of rejuvenation from the perspective of damage accumulation. In turn, this suggests approaches to achieve rejuvenation of cells in vitro and in vivo.

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“…Due to the lack of evidence of domains or sequence motifs in Tex33, it's still hard to explain which gene replaces the Tex33 in vivo yet. Recent study implies redundant testis-specific genes may not be idle or useless to the male, because the initiation of vast gene expression can prevent germ cell's DNA mutation via transcription-coupled repair (TCR), in order to avoid hereditary of wrong DNA message to the offspring (Xia et al, 2020). Our study suggests that a testis-predominantly expressed genes Tex33 is not necessary to spermatogenesis and male fertility, we should focus on genes that are indispensable to male fertility.…”

Section: Discussionmentioning

confidence: 87%

Spermatogenesis is normal in Tex33 knockout mice

Zhu

Zhang

Zeng

et al. 2020

PeerJ

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Testis expressed gene 33 (Tex33) is a recently reported testis-specific gene and it is evolutionarily conserved in vertebrates. The Tex33 expression is found in cytoplasm of round spermatids in Mus musculus. However, the in vivo function of Tex33 remains unknown. In this study, we made a 62bp in frame deletion on Exon2 of Tex33 gene by CRISPR/Cas9 in C57B/L6 mouse, which cause frame shift mutation of Tex33 gene. Tex33-/-adult male were fertile, and there is no significant change on litter size compared with male wildtype (Tex33+/+) adult. Besides, no overt differences were found in testis/body weight ratios, testicular/epididymal tissue morphology, sperm counts, sperm morphology and spermatozoa motility in adult Tex33-/-male mice (N = 3), in comparison with Tex33+/+ adult (N = 3). TUNEL assay also indicates the germ cells apoptosis ratio was not significantly changed in adult Tex33-/- adult male mouse testis (N = 3), compared with adult Tex33+/+ male (N = 3). Importantly, the first wave of elongating spermatids formation happens in 5w old mice. We find that the first wave of spermiogenesis is not disrupted in both 5-week-old Tex33+/+ and Tex33-/-male mouse testes and three hallmarks of spermatogenesis, PLZF,γ-H2AX and TNP1, are all detectable in seminiferous tubule. All results indicate that Tex33 is a redundant gene to spermatogenesis. This study can help other researchers avoid repetitive works on redundant genes.

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Widespread Transcriptional Scanning in the Testis Modulates Gene Evolution Rates

Cited by 140 publications

References 105 publications

The DNA methylome of human sperm is distinct from blood with little evidence for tissue-consistent obesity associations

The DNA methylome of human sperm is distinct from blood with little evidence for tissue-consistent obesity associations

How can aging be reversed? Exploring rejuvenation from a damage‐based perspective

Spermatogenesis is normal in Tex33 knockout mice

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