SYCP2 recruits HORMAD2 for chromosome-axis-associated ATR signaling, unsynapsed chromatin silencing, and synapsis surveillance in meiosis

ABSTRACT: Meiotic progression in mammals is governed by tightly coordinated transcriptional programs and surveillance mechanisms that ensure the successful pairing, synapsis, and segregation of homologous chromosomes. In spermatocytes, homolog pairing is safeguarded by the pachytene checkpoint, whose mechanism is critically involves meiotic sex chromosome inactivation (MSCI), a silencing mechanism that targets the largely unsynapsed X and Y chromosomes during pachytene. HORMAD2, a HORMA domain-containing protein, plays a key role in MSCI. Although in vitro studies have implicated SYCP2 in recruiting HORMAD proteins to chromosome axes, the mechanism and physiological relevance of this interaction during meiosis has remained unclear. To gain transcriptome-level insights into how loss of HORMAD2 axial recruitment affects meiotic progression and sex chromosome regulation, we performed single-cell RNA sequencing (scRNA-seq) of testicular cell suspensions of adult wild-type and Hormad2-/-mice as well as mice where SYCP2 lacked the region that is predicted to bind HORMAD2 (Sycp2e16/e16 mutant). These datasets allowed us to resolve 17 distinct germ cell states spanning the full course of spermatogenesis. We observed that, unlike wild-type cells which transcriptionally progressed into mid-pachytene and beyond, neither Sycp2e16/e16 nor Hormad2-/- spermatocytes progressed beyond an early pachytene-like transcriptional state. We also saw clear evidence of impaired meiotic sex chromosome inactivation (MSCI) in the mutants. Specifically, sex-linked gene expression abnormally persisted in the mutants resulting in overexpression of Y-linked genes Zfy1 and Zfy2, whose high expression induces spermatocyte apoptosis in mid pachytene. Related experiment can be found in S-BSST1926

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Mus musculus

SUBMITTER: Arkasarathi Gope 

PROVIDER: E-MTAB-16317 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress