Biology subjects

Esparza, J. M.

Publications and source records attributed to Esparza, J. M..

2 recordsLinked to original sources

bioRxiv2026

Paternal folate deficiency reveals meiosis as a metabolic sensing window in the male germline

Folate-dependent one-carbon metabolism supplies methyl donors required for chromatin modification, yet how metabolic conditions shape epigenome establishment in the male germline remains poorly understood. Here, using a folate-deficient mouse model, we identify meiotic prophase I as a metabolically sensitive window in the male germline. By integrating in vivo germline analysis with bulk and single-cell transcriptomic and epigenomic profiling, we show that folate deficiency disturbs transcriptional programs in pachytene spermatocytes and preferentially perturbs CpG island (CGI)-associated promoters, which are characterized by bivalent H3K4me3 and H3K27me3 during meiosis. Consistent with this selective vulnerability, active chromatin marks, including H3K4me3 and H3K27ac, are markedly reduced at CGI-associated promoters under folate-deficient conditions. Notably, loci that later exhibit altered H3K4me3 enrichment in mature sperm show earlier chromatin perturbations during meiosis, suggesting that these sperm epigenomic alterations may originate during meiotic development. Together, these findings establish a mechanistic link between paternal folate deficiency and dynamic epigenomic remodeling of CGI-associated chromatin in the male germline.

developmental biology↗

bioRxiv2023

ATF7IP2/MCAF2 directs H3K9 methylation and meiotic gene regulation in the male germline

H3K9 tri-methylation (H3K9me3) plays emerging roles in gene regulation, beyond its accumulation on pericentric constitutive heterochromatin. It remains a mystery why and how H3K9me3 undergoes dynamic regulation in male meiosis. Here, we identify a novel, critical regulator of H3K9 methylation and spermatogenic heterochromatin organization: the germline-specific protein ATF7IP2 (MCAF2). We show that, in male meiosis, ATF7IP2 amasses on autosomal and X pericentric heterochromatin, spreads through the entirety of the sex chromosomes, and accumulates on thousands of autosomal promoters and retrotransposon loci. On the sex chromosomes, which undergo meiotic sex chromosome inactivation (MSCI), the DNA damage response pathway recruits ATF7IP2 to X pericentric heterochromatin, where it facilitates the recruitment of SETDB1, a histone methyltransferase that catalyzes H3K9me3. In the absence of ATF7IP2, male germ cells are arrested in meiotic prophase I. Analyses of ATF7IP2-deficient meiosis reveal the proteins essential roles in the maintenance of MSCI, suppression of retrotransposons, and global upregulation of autosomal genes. We propose that ATF7IP2 is a downstream effector of the DDR pathway in meiosis that coordinates the organization of heterochromatin and gene regulation through the spatial regulation of SETDB1-mediated H3K9me3 deposition.

developmental biology↗