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Histone 3 (k14) acetilation in hyperbilirubinmia

ABSTRACT: Bilirubin toxicity to the CNS has been widely studied for decades, and shown impacting potential toxic/adaptation mechanisms by a significant modulation of gene expression, suggesting that mechanisms having crucial role on the regulation of gene expression, such as epigenetic mechanisms, should have a strong impact in unconjugated bilirubin toxicity. In this work, we followed the levels of histone 3 acetylation (H3K14Ac) in the cerebellum (Cll) of the developing (2, 9, 17 days after the birth and in adult age) Gunn rat (the natural model for neonatal hyperbilirubinemia and kernicterus) by Western blot, discovering an age specific alteration of the H3K14Ac in the hyperbilirubinemic animals. Then, the H3K14Ac linked chromatin was immune-precipitated and submitted to sequencing (ChIP-Seq). The GeneOntology analysis revealed that almost the 45% of H3K14Ac ChiP-Seq TSS-promoter genes were involved in the CNS development.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE109145 | GEO | 2018/09/13

REPOSITORIES: GEO

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Project description:Neonatal hyperbilirubinemia (jaundice) is common in infants, with extremely preterm infants (EPT, <28 weeks gestational age) being at high risk for bilirubin-induced neurotoxicity, resulting in neurodevelopmental impairment. Hyperbilirubinemia is treated using phototherapy to lower unconjugated bilirubin levels. However, the benefits and risks of phototherapy in EPTs have not been well studied, and bilirubin at low levels may be protective as an antioxidant. Phototherapy is associated with markers of oxidative stress in the plasma, but the effects of phototherapy on the hippocampus (HPC) are not known. Bilirubin and insults associated with EPTs impair hippocampal development, a brain structure critical for cognitive function, but their underlying mechanisms remain unknown. The effects of hyperbilirubinemia and phototherapy on the HPC were studied using a Gunn rat model. Jaundiced (jj) and non-jaundiced (Nj) pups were subjected to phototherapy from postnatal day 4 (P4) through P6. The HPC was harvested and processed for RNA sequencing. Serum bilirubin levels were elevated in jj compared to Nj control rats. Phototherapy significantly lowered serum bilirubin levels in jj rats. Compared to Nj rats, 1294 genes were differentially expressed in the jj hippocampal transcriptome and mapped onto the nervous system development, inflammation, and ferroptosis signaling pathways. Phototherapy induces 3297 differentially-expressed genes (DEGs) in rat hippocampal transcriptome compared to untreated rats. These DEGs were annotated to pathways regulating synaptogenesis, long-term potentiation, and neurogenesis. Both hyperbilirubinemia and phototherapy altered expression of 407 genes, which mapped onto hippocampal plasticity functions, including neuritogenesis and long-term potentiation. Our study demonstrates a model for investigating molecular effects of hyperbilirubemia and phototherapy in an EPT-equivalent Gunn rat pup. Our data revealed the effects of hyperbilirubinemia and phototherapy on signaling pathways critical for hippocampal development and plasticity.

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Histone 3 (k14) acetilation in hyperbilirubinmia

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