The clinical symptomatology in the X-linked Wiskott-Aldrich syndrome (WAS), a combined immunodeficiency and autoimmune disease resulting from WAS protein (WASp) deficiency, reflects the underlying coexistence of an impaired T helper 1 (T H 1) immunity alongside intact T H 2 immunity. This suggests a role for WASp in patterning T H subtype immunity, yet the molecular basis for the T H 1-T H 2 imbalance in human WAS is unknown. We have discovered a nuclear role for WASp in the transcriptional regulation of the T H 1 regulator gene TBX21 at the chromatin level. In primary T H 1-differentiating cells, a fraction of WASp is found in the nucleus, where it is recruited to the proximal promoter locus of the TBX21 gene, but not to the core promoter of GATA3 (a T H 2 regulator gene) or RORc (a T H 17 regulator gene). Genome-wide mapping demonstrates association of WASp in vivo with the gene-regulatory network that orchestrates T H 1 cell fate choice in the human T H cell genome. Functionally, nuclear WASp associates with H3K4 trimethyltransferase [RBBP5 (retinoblastoma-binding protein 5)] and H3K9/H3K36 tridemethylase [JMJD2A (Jumonji domain-containing protein 2A)] proteins, and their enzymatic activity in vitro and in vivo is required for achieving transcription-permissive chromatin dynamics at the TBX21 proximal promoter in primary differentiating T H 1 cells. During T H 1 differentiation, the loss of WASp accompanies decreased enrichment of RBBP5 and, in a subset of WAS patients, also of filamentous actin at the TBX21 proximal promoter locus. Accordingly, human WASpdeficient T H cells, from natural mutation or RNA interference-mediated depletion, demonstrate repressed TBX21 promoter dynamics when driven under T H 1-differentiating conditions. These chromatin derangements accompany deficient T-BET messenger RNA and protein expression and impaired T H 1 function, defects that are ameliorated by reintroducing WASp. Our findings reveal a

Type 2 diabetes mellitus is a multifactorial and polygenic disorder with increasing prevalence. Recently, a polymorphism in the gene encoding procolipase, a cysteine for arginine substitution at position 92, was associated with type 2 diabetes in two human populations. Because procolipase plays a critical role in dietary fat metabolism, polymorphisms that affect the function of procolipase could influence the development of type 2 diabetes. We hypothesized that the Arg92Cys polymorphism has functional consequences. To test our hypothesis, we expressed recombinant cysteine 92 (Cys92) procolipase in a yeast expression system and compared the function and stability of purified Cys92 with that of the more common arginine 92 (Arg92) procolipase. Cys92 fully restored the activity of bile-salt inhibited lipase with short-and medium-chain triglycerides but only had 50% of Arg92 function with long-chain triglycerides. After storage at 4jC, Cys92 lost the ability to restore pancreatic triglyceride lipase activity with medium-and long-chain triglycerides. The loss of function correlated with the inability of Cys92 to anchor lipase on an emulsion surface and oxidation of the cysteine. No detectable degradation or intramolecular disulfide formation occurred in Cys92 after storage. Our findings demonstrate that the Arg92Cys polymorphism decreases the function of Cys92 colipase. This change may contribute to the development of type 2 diabetes.-D'Silva, S., X. Xiao, and M. E. Lowe. A polymorphism in the gene encoding procolipase produces a colipase, Arg92Cys, with decreased function against long-chain triglycerides. Pancreatic colipase has a central role in dietary fat digestion (1). Dietary fats, of which triglycerides constitute .95%, provide 30-40% of the total caloric intake in the Western diet. Before uptake into the enterocyte and transport into the circulation, fatty acids must be released from triglycerides by lipases. Fatty acid release begins with lipolysis in the stomach and proceeds in the upper duodenum, where the majority of fatty acids are released by pancreatic triglyceride lipase (PTL). Many other constituents found in intestinal chyme, such as bile salts and phospholipids, inhibit PTL. In vitro, colipase restores activity to PTL in the presence of these inhibitors (2). In vivo, reports of colipase deficiency in humans and in mice support the role of colipase in dietary fat digestion. Both colipasedeficient humans and mice have fat maldigestion and maladsorption (1, 3).The mRNA for human colipase encodes preprocolipase, a 112 amino acid protein with a molecular mass of 11.6 kDa (4). The first 17 amino acids constitute a signal peptide. Removal of the signal peptide results in the formation of procolipase. Procolipase is the secreted form, which is converted to colipase by proteolytic cleavage, probably by trypsin, of an N-terminal pentapeptide. The peptide, called enterostatin, has been implicated in the control of voluntary fat intake (5). Berger et al. (6) proposed that enterostatin restricts fat int...