Schizosaccharomyces pombe contains two proteins, SWIRM1 and SWIRM2, with close homology to human histone H3 lysine 4 demethylase. Both proteins contain the amino oxidase catalytic domain and a recently described DNA interaction SWIRM domain. Here we describe the biochemical isolation and the functional characterization of SWIRM1 and SWIRM2. Our results indicate that while SWIRM2 is an essential gene, cells lacking SWIRM1 are viable. We found that SWIRM1 and SWIRM2 are stably associated in a multiprotein complex, but intriguingly, unlike their human counterpart, S. pombe SWIRM complex contains neither a histone deacetylase nor any detectable demethylase activity. Genome-wide chromatin immunoprecipitation unexpectedly showed the absence of both SWIRM proteins from heterochromatic domains. Instead, consistent with biochemical analyses, SWIRM1 and SWIRM2 co-localize to a common set of target gene promoters whose functions are implicated in diverse processes including mitochondrial metabolism and transcriptional regulation. Importantly, we show that SWIRM1 is not only required for optimum transcription of its target genes but also display a global role in regulation of antisense transcription.Histones, the building blocks of chromatin in eukaryotic cells, are subject to several posttranslational modifications including methylation, acetylation, phosphorylation, and ubiquitylation (1). These histone modifications play a central role in modulating chromatin structure and function (2, 3). Of particular interest in recent years, histone methylation is known to impact several cellular processes such as chromatin organization, genomic imprinting, and transcriptional regulation (4 -6). This modification occurs on five lysine (K) residues of histone H3 and one lysine residue of histone H4 that can be methylated in three different modes, i.e. mono-, di-, or trimethylation. Generally, methylated H3K4, H3K36, and H3K79 residues are thought to be activation marks, whereas methylated H3K9, H3K27, and H4K20 residues represent repressive marks (4, 7). Arginine residues can also be methylated to generally lead to transcriptional activation (5).Although other histone modifications such as acetylation, phosphorylation, and ubiquitylation have been known to be reversible, histone methylation was considered irreversible. However, recent discoveries of several histone demethylases that can reverse methylated lysine and arginine residues have altered our views of histone demethylation (8 -13). PAD4/ PADI4 was the first reported histone arginine demethylase that demethyliminates monomethylarginine to produce citrulline (8, 9). BHC110/LSD1 has been identified as the first histone lysine demethylase that removes mono-or dimethyl-H3K4 by oxidation-based demethylation (13). More recently, a new family of histone demethylases was discovered to contain a JmjC domain capable of removing methyl groups on lysine residues by hydroxylation-based demethylation (10 -12).We and others (14 -20) have purified BHC110 as a component of several multiprotein ...