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The growth hormone (GH)-GH receptor (GHR) axis modulates growth and metabolism and contributes to complications of diabetes mellitus. We analyzed the promoter region of the dominant transcript (L2) of the murine GHR to determine that a cis element, L2C1, interacts with transcription factors NF-Y, BTEB1, and HMG-Y/I. These proteins individually repress GHR expression and together form a repressosome complex in conjunction with mSin3b. The histone deacetylase inhibitor trichostatin A increases expression of the murine GHR gene, enhances association of acetyl-H3 at L2C1, inhibits formation of the repressosome complex, and decreases NF-Y's association with L2C1. Our studies reveal that murine models of experimental diabetes mellitus are characterized by reduced hepatic GHR expression, decreased acetyl-H3 associated with L2C1, and increased formation of the repressosome complex. In contrast, in the kidney diabetes mellitus is associated with enhanced GHR expression and lack of alteration in the assembly of the repressosome complex, thus permitting exposure of kidneys to the effects of elevated levels of GH in diabetes mellitus. Our findings define a higher-order repressosome complex whose formation correlates with the acetylation status of chromatin histone proteins. The delineation of the role of this repressosome complex in regulating tissue-specific expression of GHR in diabetes mellitus provides a molecular model for the role of GH in the genesis of certain microvascular complications of diabetes mellitus.The growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis plays a critical permissive role in the pathogenesis of chronic microvascular complications of diabetes mellitus (DM). The absence of functional GH receptor (GHR) confers a protective effect against diabetic nephropathy and retinopathy in murine models of insulin-dependent DM (IDDM) (2, 29). For humans, acquired hypopituitarism ameliorated retinopathy and iatrogenic hypopituitarism was the standard care for proliferative retinopathy until the advent of laser coagulation therapy (24). In contrast there is resistance to GH's actions in promoting linear growth and IGF-1 generation in poorly controlled IDDM (30); animal and human studies indicate that decreased hepatic expression of GHR contributes to this resistance to GH's actions (1,19,21). However, the molecular mechanisms underlying the paradox of the liver becoming resistant but the kidney and retina retaining sensitivity to GH in DM is not known.The GHR gene is characterized by sequence heterogeneity in the 5Ј untranslated region (UTR) (8). For the mouse, three 5Ј UTRs (L1, L2, and L5) have been characterized in some detail (20,34,36). The L2 transcript constitutes 50 to 80% of the hepatic GHR transcripts in the nonpregnant adult animal (8, 34). The 5Ј flanking region of the L2 transcript exhibits promoter activity. A cis element, L2A, interacts with the Sp family of proteins and plays a role in the development-specific expression of the GHR gene (34). Recent studies have focused attention on t...