Major histocompatibility complex class I core promoter elements are not essential for transcription in vivo.

The role of core promoter elements in regulating transcription initiation is largely unknown for genes subject to complex regulation. Major histocompatibility complex class I genes are ubiquitously expressed and governed by tissue-specific and hormonal signals. Transcription initiates at multiple sites within the core promoter, which contains elements homologous to the canonical elements CCAAT, TATAA, Sp1 binding site (Sp1BS), and Initiator (Inr). To determine their functions, expression of class I transgenes with individually mutated elements was assessed. Surprisingly, all mutant promoters supported transcription. However, each mutated core promoter element had a distinct effect on expression: CAAT box mutations modulated constitutive expression in nonlymphoid tissues, whereas TATAA-like element mutations dysregulated transcription in lymphoid tissues. Inr mutations aberrantly elevated expression. Sp1BS element mutations resulted in variegated transgene expression. RNA polymerase II binding and histone H3K4me3 patterns correlated with transgene expression; H3K9me3 marks partially correlated. Whereas the wild-type, TATAA-like, and CAAT mutant promoters were activated by gamma interferon, the Sp1 and Inr mutants were repressed, implicating these elements in regulation of hormonal responses. These results lead to the surprising conclusion that no single element is required for promoter activity. Rather, each plays a distinct role in promoter activity, chromatin structure, tissue-specific expression, and extracellular signaling.

Depressive symptoms have an independent, gradient risk for coronary heart disease incidence in a random, population-based sample.

PURPOSE: Depression is a risk factor for incident coronary heart disease (CHD), and predicts poor prognosis for patients post-myocardial infarction (MI). Few population-based, prospective studies have tested a gradient risk for depressive symptoms on CHD incidence. METHODS: The sample (n=1302) was derived from the Nova Scotia Health Survey-1995 (NSHS95), an age- and sex-stratified, random, population-based health survey. All subjects were 45 years or older, free of overt CHD at baseline, and completed the Center for Epidemiological Studies-Depression (CES-D) scale. Covariates included age, sex, body mass index, physical activity level, family history of premature CHD, diastolic blood pressure, lipids, smoking, alcohol use, diabetes, and education level. For the 4 years following NSHS95, MI-related hospitalizations (ICD-9-CM code 410) and CHD-related deaths (ICD-9-CM codes 410-414) were extracted from the provincial, universal healthcare registry. RESULTS: Fifty-two participants experienced a CHD event. A one standard-deviation increase in CES-D score was associated with a 1.32 hazard risk (confidence interval, 1.01-1.71) of CHD events, controlling for established CHD risk factors. CONCLUSIONS: An independent, gradient association between depression and incident CHD was detected in a population-based sample with complete 4-year CHD data. This evidence supports the value of investigating mechanisms linking depression and CHD.