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Patterns of histone acetylation suggest dual pathways for gene activation by a bifunctional locus control region.

ABSTRACT: The five genes of the human growth hormone (hGH) cluster are expressed in either the pituitary or placenta. Activation of the cluster is dependent on a locus control region (LCR) comprising pituitary- specific (HSI,II, -15 kb), placenta-specific (HSIV, -30 kb) and shared (HSIII, -28 kb; HSV, -32 kb) DNase I hypersensitive sites. Gene activation in the pituitary is paralleled by acetylation of a 32 kb chromatin domain 5' to the cluster centered at HSI,II. In the present study we observed that acetylation of this region in placental chromatin was discretely limited to shared HSIII and HSV. Transgenic studies revealed placenta-specific activation of linked genes by a determinant (P-element) located 2 kb 5' to each of the four placentally expressed genes. A localized peak of histone acetylation was observed at these P-elements in placenta but not pituitary. These data support a model for bifunctional action of the hGH LCR in which separate positive determinants, HSI,II and the P-elements, activate their respective target genes by tissue-specific recruitment of distinctly regulated histone acetyl transferase activities.

SUBMITTER: Elefant F

PROVIDER: S-EPMC305892 | biostudies-literature | 2000 Dec

REPOSITORIES: biostudies-literature

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Patterns of histone acetylation suggest dual pathways for gene activation by a bifunctional locus control region.

Elefant F F Su Y Y Liebhaber S A SA Cooke N E NE

The EMBO journal 20001201 24

The five genes of the human growth hormone (hGH) cluster are expressed in either the pituitary or placenta. Activation of the cluster is dependent on a locus control region (LCR) comprising pituitary- specific (HSI,II, -15 kb), placenta-specific (HSIV, -30 kb) and shared (HSIII, -28 kb; HSV, -32 kb) DNase I hypersensitive sites. Gene activation in the pituitary is paralleled by acetylation of a 32 kb chromatin domain 5' to the cluster centered at HSI,II. In the present study we observed that ace ...[more]

PMID: 11118216

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Project description:BackgroundHistone acetylation modification is one of the most common epigenetic methods used to regulate chromatin structure, DNA repair, and gene expression. Existing research has focused on the importance of histone acetylation in regulating tumorigenicity, tumor progression, and tumor microenvironment (TME) but has not explored the potential roles and interactions of histone acetylation regulators in TME cell infiltration, drug sensitivity, and immunotherapy.MethodsThe mRNA expression and genetic alterations of 36 histone acetylation regulators were analyzed in 1599 hepatocellular carcinoma (HCC) samples. The unsupervised clustering method was used to identify the histone acetylation patterns. Then, based on their differentially expressed genes (DEGs), an HAscore model was constructed to quantify the histone acetylation patterns and related subtypes of individual samples. Lastly, the relationship between HAscore and transcription background, tumor clinical features, characteristics of TME, drug response, and efficacy of immunotherapy were analyzed.ResultsWe identified three histone acetylation patterns characterized by high, medium, and low HAscore. Patients with HCC in the high HAscore group experienced worse overall survival time, and the cancer-related malignant pathways were more active in the high HAscore group, comparing to the low HAscore group. The high HAscore group was characterized by an immunosuppressive subtype because of the high infiltration of immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells. Following validation, the HAscore was highly correlated with the sensitivity of anti-tumor drugs; 116 therapeutic agents were found to be associated with it. The HAscore was also correlated with the therapeutic efficacy of the PD-L1 and PD-1 blockade, and the response ratio was significantly higher in the low HAscore group.ConclusionTo the best of our knowledge, our study is the first to provide a comprehensive analysis of 36 histone acetylation regulators in HCC. We found close correlations between histone acetylation patterns and tumor malignant pathways and TME. We also analyzed the therapeutic value of the HAscore in targeted therapy and immunotherapy. This work highlights the interactions and potential clinical utility of histone acetylation regulators in treatment of HCC and improving patient outcomes.

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Patterns of histone acetylation suggest dual pathways for gene activation by a bifunctional locus control region.

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Patterns of histone acetylation suggest dual pathways for gene activation by a bifunctional locus control region.

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