YY1 Negatively Regulates Mouse Myelin Proteolipid Protein (PLP1) Gene Expression in Oligodendroglial Cells

Abstract

YY1 (Yin and Yang 1) is a multifunctional, ubiquitously expressed, zinc finger protein that can act as a transcriptional activator, repressor, or initiator element binding protein. Previous studies have shown that YY1 modulates the activity of reporter genes driven by the myelin PLP (proteolipid protein) (PLP1/Plp1) promoter. However, it is known that Plp1 intron 1 DNA contains regulatory elements that are required for the dramatic increase in gene activity, coincident with the active myelination period of CNS (central nervous system) development. The intron in mouse contains multiple prospective YY1 target sites including one within a positive regulatory module called the ASE (anti-silencer/enhancer) element. Results presented here demonstrate that YY1 has a negative effect on the activity of a Plp1-lacZ fusion gene [PLP(+)Z] in an immature oligodendroglial cell line (Oli-neu) that is mediated through sequences present in Plp1 intron 1 DNA. Yet YY1 does not bind to its alleged site in the ASE (even though the protein is capable of recognizing a target site in the promoter), indicating that the down-regulation of PLP(+)Z activity by YY1 in Oli-neu cells does not occur through a direct interaction of YY1 with the ASE sequence. Previous studies with Yy1 conditional knockout mice have demonstrated that YY1 is essential for the differentiation of oligodendrocyte progenitors. Nevertheless, the current study suggests that YY1 functions as a repressor (not an activator) of Plp1 gene expression in immature oligodendrocytes. Perhaps YY1 functions to keep the levels of PLP in check in immature cells before vast quantities of the protein are needed in mature myelinating oligodendrocytes.

The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage

“…Two potential mechanisms have been advanced to explain the role of YY1 in myelin gene regulation: 1) YY1 is a regulator of Plp1 expression (Berndt et al, 2001; Heng et al, 2013; Zolova and Wight, 2011); 2) YY1 suppresses Id genes ( Id2 and Id4 ) and Tcf4 in OL by recruiting HDAC1 (He et al, 2007), thereby facilitating the maturation of OL cells. We explored whether these mechanisms may help explain the consequences of Thap1 loss for myelination.…”

“…We explored whether these mechanisms may help explain the consequences of Thap1 loss for myelination. We tested for THAP1 and YY1 binding at multiple predicted binding sites in Plp1 : (1) promoter, (2) putative THAP1 binding sites and (3) “ASE” (anti-silencer/enhancer), an intronic regulatory site reported to be responsible for YY1 mediated repression of Plp1 (Zolova and Wight 2011). We detected no THAP1 or YY1 binding at any of these sites in OL (Figure 6F–G).…”

mTOR: A Link from the Extracellular Milieu to Transcriptional Regulation of Oligodendrocyte Development

“…Conditional ablation of YY1 in oligodendrocytes results in reduced OPC differentiation and myelination (He et al, 2007). Recent studies in the Oli-Neu glial cell line suggests that YY1 may also function later in the oligodendrocyte differentiation programme to inhibit PLP gene expression at the immature OL stage (Zolova and Wight, 2011). …”

miR-200b and Cancer/Testis Antigen CAGE Form a Feedback Loop to Regulate the Invasion and Tumorigenic and Angiogenic Responses of a Cancer Cell Line to Microtubule-targeting Drugs

“…YY1 interacts with HDAC2 and regulates the expression of human B type natriuretic peptide (30). YY1 negatively regulates the mouse myelin proteolipid protein (Plp1) gene (31). YY1 represses muscle miRNA expression in myoblasts, and the repression is mediated through multiple enhancers and the recruitment of Polycomb complex to several YY1-binding sites (32).…”