Myt1 family recruits histone deacetylase to regulate neural transcription
Abstract
The myelin transcription factor 1 (Myt1) gene family is comprised of three zinc finger genes [Myt1, Myt1L (Myt1-Like) and NZF3] of the structurally unique CCHHC class that are expressed predominantly in the developing CNS. To understand the mechanism by which this family regulates neural differentiation, we searched for interaction partners. In both yeast and a mammalian two-hybrid system, Myt1 and Myt1L interacted with Sin3B, a protein that mediates transcriptional repression by binding to histone deacetylases (HDACs). Myt1–Sin3B complexes were co-immunoprecipitated from transfected mammalian cells and included HDAC1 and HDAC2. Myt1 and Myt1L could partner with all three Sin3B isoforms, the long form (Sin3BLF) that includes the HDAC-binding domain, and the two short forms (Sin3BSF293 and Sin3BSF302) that lack this domain and may consequently antagonize Sin3BLF/HDAC-mediated co-repression. Myt1 or Myt1L interactions with the HDAC-binding form of Sin3B conferred repression on a heterologous promoter. Oligodendrocytes were shown to express transcripts encoding each of the Sin3B isoforms. We present a model in which the Myt1 family of zinc finger proteins, when bound to a neural promoter, can recruit Sin3B. Depending on the relative availability of Sin3B isoforms, the Myt1 gene family may favor the silencing of genes during neural development.
The specification and differentiation of neural cells is orchestrated at the transcriptional level by two classes of factors, those with chromatin-remodeling activities that regulate how tightly histones wrap up DNA in nucleosomal structures, and those that directly contact target genes and/or other transcription factors and ultimately determine whether the basal machinery initiates transcription. These two classes are functionally and physically linked, as co-activator complexes have an associated histone acetylase whose activity relaxes chromatin structure to promote accessibility of DNA-binding proteins, and co-repressor complexes have an opposing histone deacetylase (HDAC) activity (Wolffe et al. 2000). Key to this linkage are sequence-specific transcription factors that can recruit HDACs or acetylases. The zinc finger protein RE1-silencing transcription factor is one such factor that represses many neuron-specific genes through multiple HDAC complexes (Grimes et al. 2000; Ballas et al. 2001).
The myelin transcription factor 1 (Myt1) family represents neural zinc finger proteins of a structurally novel CCHHC class that were originally cloned by their binding to the promoter of the most abundantly expressed myelin gene, proteolipid protein (Kim and Hudson 1992). The consensus DNA-binding domain of the Myt1 family is Cys-X4-Cys-X4-His-X7-His-X5-Cys (also termed CCHHC domains). A novel fold arises from the coordination of a zinc ion to the three Cys residues and the second His residues, whereas the other conserved His residue is stacked between the zinc-coordinated His and an aromatic residue (Berkovits-Cymet et al. 2004).
Myt1 modulates the proliferation and differentiation of oligodendrocytes, the myelin-forming cell of the CNS (Nielsen et al. 2004). Moreover, overexpressed Myt1 promotes commitment to a neuronal fate in Xenopus (Bellefroid et al. 1996). Two additional Myt1 family members with selective neural expression were subsequently identified: Myt1-Like (Myt1L/neural zinc finger(NZF)-1/Png-1) and NZF-3/rMyT3 (Bellefroid et al. 1996; Jiang et al. 1996; Kim et al. 1997; Weiner and Chun 1997; Yee and Yu 1998). Both activator and repressor activities have been reported for the Myt1 family in transient transfection assays (Bellefroid et al. 1996; Jiang et al. 1996; Yee and Yu 1998). To define how the Myt1 family contributes to neural differentiation, we examined the interactions of Myt1 with other nuclear partners. Both Myt1 and Myt1L interacted with the co-repressor Sin3B, and the Myt1 complexes were shown to include HDAC1 and HDAC2. The Myt1 family exemplifies a class of neural sequence-specific transcription factors that actively recruit HDACs to selected genes during CNS development.