Briley, S. M. | Search bioRxiv

bioRxiv2022

The E2 SUMO-conjugating enzyme UBE2I coordinates the oocyte and zygotic transcriptional programs

In mammals, meiotically competent oocytes develop cyclically during ovarian folliculogenesis. During folliculogenesis, prophase I arrested oocytes are transcriptionally active, producing and storing transcripts required for their growth and for early stages of embryogenesis prior to the maternal to zygotic transition. Defective oocyte development during folliculogenesis leads to meiotic defects, aneuploidy, follicular atresia, or non-viable embryos. Here we generated a novel oocyte-specific knockout of the SUMO E2 ligase, Ube2i, using Zp3-cre to test its function during folliculogenesis. Ube2i Zp3-cre+ female mice are sterile with oocytes that arrest in meiosis I with defective spindles and chromosome alignment. Fully grown mutant oocytes abnormally maintain transcription but downregulate maternal effect genes and prematurely activate the zygotic transcriptional program. Thus, this work uncovers UBE2i as a novel orchestrator of chromatin and transcriptional regulation in mouse oocytes. TeaserOocyte-specific deletion of Ube2i causes loss of transcriptional repression and premature activation of the zygotic genome.

cell biology↗

bioRxiv2020

Ubc9 deletion in adipocytes causes lipoatrophy in mice

ObjectiveWhite adipose tissue (WAT) expansion regulates energy balance and overall metabolic homeostasis. WAT absence or loss occurring through lipodystrophy and lipoatrophy contributes to the development of dyslipidemia, hepatic steatosis, and insulin resistance. We previously demonstrated the sole small ubiquitin-like modifier (SUMO) E2-conjuguating enzyme Ubc9 represses human adipocyte differentiation. Germline and other tissue-specific deletions of Ubc9 frequently cause lethality in mice. As a result, the role of Ubc9 during WAT development remains unknown. MethodsTo determine how Ubc9 impacts body composition and energy balance, we generated adipocyte-specific Ubc9 knockout mice (Ubc9a-KO). CRISPR/Cas9 gene editing inserted loxP sites flanking exons 3 and 4 at the Ubc9 locus. Subsequent genetic crosses to AdipoQ-Cre transgenic mice allowed deletion of Ubc9 in white and brown adipocytes. We measured multiple metabolic endpoints that describe energy balance and carbohydrate metabolism in Ubc9a-KO and littermate controls during postnatal growth. ResultsTo our surprise, Ubc9a-KO mice developed hyperinsulinemia and hepatic steatosis. Global energy balance defects emerged from dysfunctional WAT marked by pronounced local inflammation, loss of serum adipokines, hepatomegaly, and near absence of major adipose tissue depots. We observed progressive lipoatrophy that commences in the early adolescent period. ConclusionsOur results demonstrate that Ubc9 expression in mature adipocytes is essential for maintaining WAT expansion. Deletion of Ubc9 in fat cells compromised and diminished adipocyte function that provoked WAT inflammation and ectopic lipid accumulation in the liver. Our findings reveal an indispensable role for Ubc9 during white adipocyte expansion and endocrine control of energy balance.

developmental biology↗