Biology subjects

Brind'Amour, J.

Publications and source records attributed to Brind'Amour, J..

4 recordsLinked to original sources

bioRxiv2026

Cell-type-specific decoding of Hippo pathway inactivation drives seminiferous epithelial collapse and rete testis hyperplasia in the adult mouse testis

The Hippo pathway is a major regulator of epithelial homeostasis, but its role in the adult testis remains poorly defined. Here, we conditionally deleted Lats1 and Lats2 in WT1-expressing cells of the adult mouse testis, targeting both Sertoli cells and rete testis epithelial cells. Deletion of Lats1/2 caused rapid degeneration of the seminiferous epithelium, leading to near-complete germ cell loss, while simultaneously inducing marked hyperplasia of the rete testis. These tissue alterations were accompanied by vascular remodeling, macrophage accumulation, and extracellular matrix deposition. Cell-type-resolved transcriptomic analyses showed that Sertoli cells and rete testis epithelial cells have distinct baseline identities that shape their response to Hippo pathway inactivation. While both lineages activated shared YAP/TAZ-responsive genes, their broader outputs diverged sharply, with Sertoli cells preferentially activated structural remodeling programs, whereas rete testis epithelial cells robustly activated cell-cycle pathways and lost ciliogenesis-associated features. Regulatory network analysis further identified a conserved Hippo-responsive transcriptional backbone that was redeployed through lineage-specific regulons in each cell type. Together, these findings identify LATS1/2-mediated Hippo signaling as an essential regulator of adult testicular epithelial homeostasis and show that neighboring epithelial lineages decode Hippo pathway disruption through distinct transcriptional programs, resulting in divergent pathological outcomes.

cell biology↗

bioRxiv2020

Maternal DNMT3A-dependent de novo methylation of the zygotic paternal genome inhibits gene expression in the early embryo

De novo DNA methylation (DNAme) during mammalian spermatogenesis yields a densely methylated genome, with the exception of CpG islands (CGIs), which are hypomethylated in sperm. Following fertilization, the paternal genome undergoes widespread DNAme loss before the first S-phase. Paradoxically, recent mass spectrometry analysis revealed that a low level of de novo DNAme occurs exclusively on the zygotic paternal genome. However, the loci involved and impact on genic transcription was not addressed. Here, we employ allele-specific analysis of wholegenome bisulphite sequencing (WGBS) data and show that a number of genomic regions, including several dozen CGI promoters, are de novo methylated on the paternal genome in 2-cell embryos. A subset of these promoters maintains DNAme through development to the blastocyst stage. Consistent with zygotic paternal DNAme acquisition (PDA), many of these loci are hypermethylated in androgenetic blastocysts but hypomethylated in parthenogenetic blastocysts. Strikingly, PDA is lost following maternal deletion of Dnmt3a. Furthermore, a subset of promoters showing PDA which are normally transcribed from the paternal allele in blastocysts show premature transcription at the 4-cell stage in maternal Dnmt3a knockout embryos. These observations uncover an unexpected role for maternal DNMT3A activity in postfertilization epigenetic reprogramming and transcriptional silencing of the paternal genome.

developmental biology↗

bioRxiv2019

The majority of histone acetylation is a consequence of transcription

Histone acetylation is a ubiquitous hallmark of transcriptional activity, but whether the link is of a causal or consequential nature is still a matter of debate. In this study we resolve this question. Using both immunoblot analysis and chromatin immunoprecipitation-sequencing (ChIP-seq) in S. cerevisiae, we show that the majority of histone acetylation is dependent on transcription. Loss of histone H4 acetylation upon transcription inhibition is partially explained by depletion of histone acetyltransferases (HATs) from gene bodies, implicating transcription in HAT targeting. Despite this, HAT occupancy alone poorly predicts histone acetylation, suggesting that HAT activity is regulated at a step post-recruitment. Collectively, these data show that the majority of histone acetylation is a consequence of RNAPII promoting both the recruitment and activity of histone acetyltransferases.

molecular biology↗

bioRxiv2019

Evolution of imprinting via lineage-specific insertion of retroviral promoters

Imprinted genes are expressed from a single parental allele. In mammals, this unusual mode of transcription generally depends on the epigenetic silencing of one allele by DNA methylation (DNAme) established in the germline. While many species-specific imprinted orthologues have been documented in eutherians, the molecular mechanisms underlying the evolutionary switch from biallelic to imprinted expression are currently unknown. During mouse oogenesis, gametic differentially methylated regions (gDMRs) acquire DNAme in a process guided by transcription. Here we show that transcription initiating in proximal lineage-specific endogenous retroviruses (ERVs) is likely responsible for DNAme established in oocytes at 4/6 mouse-specific and 17/110 human-specific maternal imprinted gDMRs (igDMRs). The latter can be further divided into Catarrhini (Old World monkeys and apes)- or Hominoidea (ape)-specific igDMRs, which are embedded within transcription units initiating in ERVs specific to these primate lineages. Using CRISPR-Cas9 mutagenesis, we deleted the relevant murine-specific ERVs upstream of the maternally methylated genes Impact and Slc38a4. Strikingly, imprinting at these genes was lost in the offspring of females harboring these deletions and biallelic expression was observed. Our work reveals a novel evolutionary mechanism whereby maternally silenced genes arise from biallelically expressed progenitors.

genetics↗