Swaminathan Jyothishmathi, Maegawa Shinji, Shaik Shavali, Sharma Ajay, Bravo-Alegria Javiera, Guo Lei, Xu Lin, Harmanci Arif, Gopalakrishnan Vidya
Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX, United States.
Quantitative Biomedical Research Center, Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, United States.
Front Oncol. 2022 May 6;12:855167. doi: 10.3389/fonc.2022.855167. eCollection 2022.
The Silencing Transcription Factor (REST) is a major regulator of neurogenesis and brain development. Medulloblastoma (MB) is a pediatric brain cancer characterized by a blockade of neuronal specification. gene expression is aberrantly elevated in a subset of MBs that are driven by constitutive activation of sonic hedgehog (SHH) signaling in cerebellar granular progenitor cells (CGNPs), the cells of origin of this subgroup of tumors. To understand its transcriptional deregulation in MBs, we first studied control of gene expression during neuronal differentiation of normal mouse CGNPs. Higher expression was observed in proliferating CGNPs compared to differentiating neurons. Interestingly, two isoforms were expressed in CGNPs, of which only one showed a significant reduction in expression during neurogenesis. In proliferating CGNPs, higher MLL4 and KDM7A activities opposed by the repressive polycomb repressive complex 2 (PRC2) and the G9A/G9A-like protein (GLP) complex function allowed homeostasis. During differentiation, reduction in MLL4 enrichment on chromatin, in conjunction with an increase in PRC2/G9A/GLP/KDM7A activities promoted a decline in expression. These findings suggest a lineage-context specific paradoxical role for KDM7A in the regulation of expression in CGNPs. In human SHH-MBs (SHH-α and SHH-β) where elevated REST gene expression is associated with poor prognosis, up- or downregulation of caused a significant worsening in patient survival. Our studies are the first to implicate KDM7A in regulation and in MB biology.
沉默转录因子（REST）是神经发生和大脑发育的主要调节因子。髓母细胞瘤（MB）是一种小儿脑癌，其特征在于神经元特化受阻。在一小部分MB中，该基因的表达异常升高，这些MB由小脑颗粒祖细胞（CGNP）中 Sonic Hedgehog（SHH）信号的组成性激活驱动，CGNP是该肿瘤亚组的起源细胞。为了了解其在MB中的转录失调，我们首先研究了正常小鼠CGNP神经元分化过程中该基因表达的调控。与分化中的神经元相比，在增殖的CGNP中观察到更高的该基因表达。有趣的是，在CGNP中表达了两种该基因的异构体，其中只有一种在神经发生过程中表达显著降低。在增殖的CGNP中，更高的MLL4和KDM7A活性与抑制性多梳抑制复合物2（PRC2）以及G9A/G9A样蛋白（GLP）复合物的功能相互拮抗，从而实现该基因的稳态。在分化过程中，染色质上MLL4富集的减少，与PRC2/G9A/GLP/KDM7A活性的增加共同促进了该基因表达的下降。这些发现表明KDM7A在CGNP中该基因表达的调控中具有谱系背景特异性的矛盾作用。在人类SHH-MB（SHH-α和SHH-β）中，REST基因表达升高与预后不良相关，该基因的上调或下调都会导致患者生存率显著恶化。我们的研究首次表明KDM7A参与该基因的调控以及MB生物学过程。
