The histone deacetylase domain of almost all members of higher eukaryotic histone deacetylases already identified (HDAC family) is highly homologous to that of yeast RPD3. In this paper we report the cloning of two cDNAs encoding members of a new family of histone deacetylase in mouse that show a better homology to yeast HDA1 histone deacetylase. These cDNAs encode relatively large proteins, presenting an in vitro trichostatin A-sensitive histone deacetylase activity. Interestingly, one, mHDA2, encodes a protein with two putative deacetylase domains, and the other, mHDA1, contains only one deacetylase homology domain, located at the C-terminal half of the protein. Our data showed that these newly identified genes could belong to a network of genes coordinately regulated and involved in the remodeling of chromatin during cell differentiation. Indeed, the expression of mHDA1 and mHDA2 is tightly linked to the state of cell differentiation, behaving therefore like the histone H1 degrees-encoding gene. Moreover, like histone H1(0) gene, mHDA1 and mHDA2 gene expression is induced upon deacetylase inhibitor treatment. We postulate the existence of a regulatory mechanism, commanding a coordinate expression of a group of genes involved in the remodeling of chromatin not only during cell differentiation but also after abnormal histone acetylation.