Leukemia/lymphoma‐related factor (LRF) exhibits stage‐ and context‐dependent transcriptional controls in the oligodendrocyte lineage and modulates remyelination
In the environment of demyelinated lesions, reactive astrocytes and activated microglia/macrophages express molecular signals that act, through transcriptional controls, to regulate OP differentiation (Gallo & Deneen, 2014). Multiple transcription factors that regulate OP differentiation can interact with histone deacetylase 1 (HDAC1), including leukemia/lymphoma‐related factor (LRF), myelin transcription factor 1, and Yin‐Yang1 (Armstrong, Kim, & Hudson, 1995; Dobson, Moore, Tobin, & Armstrong, 2012; He, Sandoval, & Casaccia‐Bonnefil, 2007; Liu et al., 2004; Nielsen, Berndt, Hudson, & Armstrong, 2004; Romm, Nielsen, Kim, & Hudson, 2005). Each of these potential transcriptional repressors exhibits stage‐specific expression within the oligodendrocyte lineage. In addition, HDAC1 represses the transcription factor Hes5 to promote OP differentiation and mediate derepression of myelin genes (Liu et al., 2006; Shen et al., 2008).
The notch‐signaling pathway is one of the potent inhibitors of OP differentiation that limit remyelination (Hammond et al., 2014; Zhang et al., 2009). Jagged1, a notch ligand, is expressed in hypertrophic astrocytes in active multiple sclerosis plaques lacking remyelination (John et al., 2002). Notch1 acts through Hes5 to inhibit OP differentiation (Wu, Liu, Levine, & Rao, 2003). Hes5 is progressively down‐regulated during OP differentiation yet elevated in demyelinated lesions in which remyelination is limited, such as in chronic lesions of multiple sclerosis (John et al., 2002; Kondo & Raff, 2000; Liu et al., 2006; Wang et al., 1998).
LRF warrants particular interest as a potential point of intersection between HDAC1 promoter regulation and notch signaling. LRF has been referred to as the “most exciting yet enigmatic” member of the POK/ZBTB family of transcription factors, which generally act as transcriptional repressors (Lunardi, Guarnerio, Wang, Maeda, & Pandolfi, 2013). The 43 known members of this protein family contain a POK/BTB domain at the N terminus, which mediates protein‐protein interactions, while the C terminus contains multiple Kruppel‐type zinc fingers that bind DNA. The gene zinc finger and BTB domain‐containing protein 7A (Zbtb7a) encodes the protein referred to as LRF (mouse), OCZF (rat), or FBI‐1 (human) and will be referred to as LRF here. LRF binds corepressors and recruits HDAC1 to gene targets with consensus LRF binding sites (Liu et al., 2004; Lunardi, Guarnerio, Wang, Maeda, & Pandolfi, 2013). LRF plays a critical role in promoting differentiation of B cells by suppressing Notch1 signals that instruct differentiation along the T cell lineage (Lee et al., 2013; Maeda et al., 2007). In multiple cell lines, LRF also interacts with sterol regulatory element‐binding protein (SREBP) to synergistically activate transcription of fatty acid synthase (FASN), which is essential for phospholipids in myelin and cell membranes (Choi et al., 2008). In OP cells, SREBPs are important regulators of oligodendrocyte maturation and FASN levels (Monnerie et al., 2017). However, LRF activity can be stage‐specific as shown for transcriptional regulation in the osteoclast lineage and also for fetal to adult type globin gene expression in erythroid cells (Masuda et al., 2016; Tsuji‐Takechi et al., 2012).