Biomedical subjects

Sean T Kim

Publications and source records attributed to Sean T Kim.

6 recordsLinked to original sources

PubMed2006

Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse.

To identify interleukin-10 (IL-10)-producing cells in vivo, we generated a knockin mouse where an internal ribosome entry site (IRES) green fluorescence protein (GFP) element was inserted immediately before the polyadenylation site of the IL-10 gene. GFP fluorescence in cells from these mice was found to correlate positively with IL-10 protein expression. With this model, we found that after multiple T cell receptor (TCR) stimulations, strong expression of IL-10 was produced specifically by intraepithelial lymphocytes (IEL) in the small intestine and colonic lamina propria lymphocytes (cLPL). We found that anti-CD3 treatment induces T regulatory cell 1 (Tr1)-like cells in small intestinal IEL (sIEL) and led to the accumulation of naturally occurring regulatory T (nTreg) cells in colonic LPL (cLPL). These findings highlight the intestine as a unique site for induction of IL-10-producing T cells, which play a critical role in the regulation of inflammation in the gut.

Adoptive Transfer↗

PubMed2006

T helper cell differentiation: regulation by cis elements and epigenetics.

Cytokine loci undergo changes in chromatin structure when naive CD4(+) T cells differentiate into Th1 or Th2 cells and have also been examined for regulatory sequences underlying such changes and their functional correlates. Studies have shown that distal regulatory elements control the Ifng and Th2 cytokine loci and are primary targets for tissue-specific transcription factors, serving as centers for epigenetic changes that mark heritable traits in effector cells. Reports of intra- and, remarkably, interchromosomal interactions between these regulatory elements shed light on the mechanisms by which they regulate gene expression, revealing an extraordinary new picture that conceptually extends our views on how genes are regulated from two to three dimensions. Here, we summarize these recent findings on the role of regulatory elements and their mechanisms of action, which are of broad significance for gene regulation, not only of the immune system but also of many, if not all, coregulated genes.

Animals↗

PubMed2005

Histone modifications associated with somatic hypermutation.

A number of modified histones, including acetylated H3 and H4 and phosphorylated H2AX (gammaH2AX), are associated with V(D)J recombination and class switch recombination (CSR). In contrast, little is known concerning the chromatin modifications associated with somatic hypermutation (SHM) in vivo. Here, we report that several modifications--including histone acetylation and H3-lysine 4 methylation--fail to demarcate an actively hypermutating immunoglobulin (Ig) locus or to correlate spatially with SHM within Ig loci. Furthermore, no obvious association between SHM and gammaH2AX could be detected. Instead, we find that the phosphorylated form of histone H2B (H2B(Ser14P)) correlates tightly with SHM and CSR. Phosphorylation of H2B within Ig variable and switch regions requires AID and may be mediated by the histone kinase Mst1. These findings indicate that SHM and CSR trigger distinct DNA damage responses and identify a novel histone modification pattern for SHM consisting of H2B(Ser14P) in the absence of gammaH2AX.

Acetylation↗

PubMed2004

Th2-specific chromatin remodeling and enhancer activity in the Th2 cytokine locus control region.

We recently identified a 3' region of the rad50 gene possessing strong enhancer activity as well as activity consistent with function as a locus control region (LCR) for the flanking Th2 cytokine genes. In this study, we identify several functional elements within this region by examining chromatin changes as well as activity in transgenic mice. We find within this region four DNase I hypersensitive clusters, three of which are highly conserved and predominantly expressed in Th2 cells. Histone acetylation of this region is elevated in Th2 cells. Further, one of the hypersensitive sites (RHS7) is rapidly demethylated in Th2, but not Th1, cells. In transgenic mice, these hypersensitive sites impart strong, Th2-specific enhancer activity as well as copy number-dependent expression of the reporter gene, recapitulating LCR function. We postulate that these sites function alone or in combination with other regulatory elements to coordinate gene expression in the Th2 cytokine locus.

ATP-Binding Cassette Transporters↗

PubMed2002

Cutting edge: changes in histone acetylation at the IL-4 and IFN-gamma loci accompany Th1/Th2 differentiation.

Peripheral T cell differentiation is accompanied by chromatin changes at the signature cytokine loci. Using chromatin immunoprecipitation we demonstrate that profound increases in histone acetylation occur at the IFN-gamma and IL-4 loci during Th1/Th2 differentiation. These changes in histone acetylation status are locus and lineage specific, and are maintained by the transcription factors Tbet and GATA3 in a STAT-dependent manner. Our results suggest a model of cytokine locus activation in which TCR signals initiate chromatin remodeling and locus opening in a cytokine-independent fashion. Subsequently, cytokine signaling reinforces polarization by expanding and maintaining the accessible state at the relevant cytokine locus (IL-4 or IFN-gamma). In this model, GATA3 and Tbet serve as transcriptional maintenance factors, which keep the locus accessible to the transcriptional machinery.

Acetylation↗

PubMed2002

A mammalian homolog of Drosophila schnurri, KRC, regulates TNF receptor-driven responses and interacts with TRAF2.

The cytokine TNFalpha launches cascades of gene activation that control inflammation and apoptosis through NFkappaB and JNK/SAPK signal transduction pathways. Here we describe a function for the zinc finger transcription factor kappa recognition component (KRC) in regulating patterns of gene activation in response to proinflammatory stimuli. We demonstrate that KRC overexpression inhibits while antisense or dominant-negative KRC enhances NFkappaB-dependent transactivation and JNK phosphorylation and consequently, apoptosis and cytokine gene expression. The effect of KRC is mediated through its interaction with the adaptor protein TRAF2, which intersects both pathways. KRC is a hitherto unrecognized participant in the signal transduction pathway leading from the TNF receptor to gene activation and may play a critical role in inflammatory and apoptotic responses.

3T3 Cells↗