Protein kinase A promotes beige adipogenesis downstream from β-adrenergic receptor signaling by phosphorylating proteins, including histone H3 lysine 9 (H3K9) demethylase JMJD1A. To ensure homeostasis, this process needs to be reversible however, this step is not well understood. We show that myosin phosphatase target subunit 1- protein phosphatase 1β (MYPT1-PP1β) phosphatase activity is inhibited via PKA-dependent phosphorylation, which increases phosphorylated JMJD1A and beige adipogenesis. Mechanistically, MYPT1-PP1β depletion results in JMJD1A-mediated H3K9 demethylation and activation of the Ucp1 enhancer/promoter regions. Interestingly, MYPT1-PP1β also dephosphorylates myosin light chain which regulates actomyosin tension-mediated activation of YAP/TAZ which directly stimulates Ucp1 gene expression. Pre-adipocyte specific Mypt1 deficiency increases cold tolerance with higher Ucp1 levels in subcutaneous white adipose tissues compared to control mice, confirming this regulatory mechanism in vivo. Thus, we have uncovered regulatory cross-talk involved in beige adipogenesis that coordinates epigenetic regulation with direct activation of the mechano-sensitive YAP/TAZ transcriptional co-activators.
Enhancer activation is essential for cell-type specific gene expression during cellular differentiation, however, how enhancers transition from a hypoacetylated “primed” state to a hyperacetylated-active state is incompletely understood. Here, we show SET domain-containing 5 (SETD5) forms a complex with NCoR-HDAC3 co-repressor that prevents histone acetylation of enhancers for two master adipogenic regulatory genes Cebpa and Pparg early during adipogenesis. The loss of SETD5 from the complex is followed by enhancer hyperacetylation. SETD5 protein levels were transiently increased and rapidly degraded prior to enhancer activation providing a mechanism for the loss of SETD5 during the transition. We show that induction of the CDC20 co-activator of the ubiquitin ligase leads to APC/C mediated degradation of SETD5 during the transition and this operates as a molecular switch that facilitates adipogenesis.
OBJECTIVEVisual acuity impairment due to sellar and suprasellar tumors is not fully understood. The relationship between these tumors and disturbance of visual function was examined using preoperative MRI.METHODSThis study reviewed 93 consecutive patients with sellar and suprasellar tumors. Best-corrected visual acuity (BCVA) and visual impairment score (VIS) were used for estimation of visual impairments. Preoperative MR images were examined to obtain several values for estimation of chiasmatic compression. Additionally, the optic nerve–canal bending angle (ONCBA) was newly defined as the external angle formed by the optic nerve in the optic canal and the optic nerve in the intracranial subarachnoid space at the junction, using preoperative sagittal T2-weighted MR images.RESULTSThe mean ONCBA was about the same on the right (44° ± 25°) and the left (44° ± 24°). Sagittal ONCBA was defined as large (> 45°) and moderate (≤ 45°) on each side. Preoperative VIS was found to be significantly worse if the right or left ONCBA (or both) was large (right side: ONCBA large [median 20, IQR 8–30] > ONCBA moderate [median 10, IQR 3–17], p = 0.003, Mann-Whitney U-test; left side: ONCBA large [median 22, IQR 9–30] > ONCBA moderate [median 10, IQR 2–16], p = 0.001). A large ONCBA showed a significant relationship with unfavorable ipsilateral BCVA (> logMAR, 0; right side, p = 0.001, left side, p = 0.001, chi-square test). The ONCBA had a positive correlation with ipsilateral BCVA (right: r = 0.297, p = 0.031; left: r = 0.451, p = 0.000, Pearson’s correlation coefficient). Preoperative BCVA was significantly lower on the same side in the large ONCBA group compared with the moderate ONCBA group (right side: large ONCBA 0.169 ± 0.333 [logMAR, mean ± standard deviation] vs moderate ONCBA 0.045 ± 0.359, p = 0.026, Student t-test; left side: large ONCBA 0.245 ± 0.346 vs moderate ONCBA 0.025 ± 0.333, p = 0.000). This visual acuity impairment improved after resection of the tumors.CONCLUSIONSSagittal bending of the optic nerve at the entrance from the intracranial subarachnoid space to the optic canal may be related to ipsilateral deterioration of visual acuity in sellar and suprasellar lesions. Sagittal T2-weighted MRI is recommended for preoperative estimation of the optic nerve bending.
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