The myelin transcription factor 1 (Myt1) gene family is comprised of three zinc finger genes [Myt1, 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 twohybrid system, Myt1 and Myt1L interacted with Sin3B, a protein that mediates transcriptional repression by binding to histone deacetylases (HDACs). Myt1-Sin3B complexes were coimmunoprecipitated from transfected mammalian cells and included HDAC1 and HDAC2. Myt1 and Myt1L could partner with all three Sin3B isoforms, the long form (Sin3B LF ) that includes the HDAC-binding domain, and the two short forms (Sin3B SF293 and Sin3B SF302 ) that lack this domain and may consequently antagonize Sin3B LF /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.Keywords histone deacetylase; mSin3; Myt1; repression; transcription; zinc finger Abbreviations usedCMV, cytomegalovirus; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HDAC, histone deacetylase; Myt1, myelin transcription factor 1; Myt1L, myelin transcription factor 1 like; NZF, neural zinc finger; PAH, paired amphipathic helicalThe 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 sequencespecific 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-X 4 -Cys-X 4 -His-X 7 -His-X 5 -Cy...