IL-10 is a potent anti-inflammatory cytokine interfering with antigen presentation by inducing the intracellular sequestration of MHC class II (MHC-II) molecules. Here we studied the contribution of membrane-associated RING-CH (MARCH) ubiquitin ligase family members to the IL-10-induced down-regulation of MHC-II molecules. We found that MARCH1 and MARCH8 proteins are the most potent family members for the downregulation of MHC-II surface expression in transfected cells, but only MARCH1 mRNA expression is strongly induced by IL-10 in human primary monocytes. We detected monoand poly-ubiquitinated forms of MHC-II molecules both in IL-10-treated monocytes and in cells transfected with MARCH1. We also show direct interaction between MHC-II and MARCH1 molecules in co-immunoprecipitation assays. Finally, we found that siRNAmediated knockdown of MARCH1 reverses IL-10-induced MHC-II down-regulation in primary monocytes. Thus, the immunosuppressive effect of IL-10 on antigen presentation is mediated through induced expression of MARCH1.

To study epigenetic regulation of the human ␤-globin locus during hematopoiesis, we investigated patterns of histone modification and chromatin accessibility along this locus in hematopoietic progenitor cells (HPCs) derived from both humans and transgenic mice. We demonstrate that the developmentally related activation of human ␤-like globin genes in humans and transgenic mice HPCs is preceded by a wave of gene-specific histone H3 hyperacetylation and K4 dimethylation. In erythroid cells, expression of ␤-like globin genes is associated with histone hyperacetylation along these genes and, surprisingly, with local deacetylation at active promoters. We also show that endogenous mouse ␤ major and human ␤-like genes are subject to different epigenetic control mechanisms in HPCs. This difference is likely due to intrinsic properties of the human ␤-globin locus since, in transgenic mice, this locus is epigenetically regulated in the same manner as in human HPCs. Our results suggest that a defined pattern of histone H3 acetylation/dimethylation is important for specific activation of human globin promoters during development in human and transgenic HPCs. We propose that this transient acetylation/dimethylation is involved in gene-specific potentiation in HPCs (ie, before extensive chromatin remodeling and transcription take place in erythroid cells). IntroductionRegulation of the "on/off" state of transcription in eukaryotes plays a critical role in embryogenesis and cellular differentiation. 1 This heritable process is linked to epigenetic states involving DNA methylation and changes in chromatin structure, which maintain transcriptional status throughout mitosis and DNA replication. Eukaryotic gene activation results from the interplay of trans-activators and/or repressors with nucleosome-modifying and/or -remodeling factors. Indeed, nucleosome organization is a key component of epigenetic regulation (Felsenfeld and Groudine 2 and references therein). Observations made in recent years have led to the notion that a combination of histone modifications such as acetylation, phosphorylation, and methylation generates a histone code that regulates the use of information from the genetic code. 3 These posttranslational modifications of histones are important determinants in nucleosome-nucleosome and nucleosome-DNA interactions 4 and provide precise patterns recognized and bound by specific proteins.Epigenetic regulation of transcription appears to play an important role during hematopoiesis. For example, abnormal patterns of DNA methylation and chromatin structure are common traits in hematologic malignancies, 5 and chromosomal translocations that change the activity of histone acetyltransferases and histone deacetylases (HDACs) are associated with several forms of leukemia. 6 Hematopoiesis is characterized by a gradual commitment of multipotent hematopoietic progenitors to become bipotent or unipotent progenitors and, eventually, mature blood cells. In hematopoietic progenitor cells (HPCs), lineage-specific genes are thou...