# Long Noncoding RNA H19 Mediating Alternative Splicing in ALD Pathogenesis

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $400,881

## Abstract

Project Summary
Excessive alcohol consumption is a leading cause of alcohol-associated liver disease (ALD). ALD is a major
public health issue in the US due to its rising incidence and prevalence. A better understanding of the
mechanism of ALD pathogenesis is critical and may pave a way to identify potential therapeutic targets. H19 is
a long noncoding RNA; its expression is highly upregulated in the liver of patients with ALD and ethanol-fed
mice. However, the mechanism of H19 in ALD pathogenesis has not been fully explored. Our overarching
objective of this grant application is to understand the mechanism of H19 mediated alcohol-induced liver injury.
For specific aim#1, we plan to determine the molecular mechanism on alcohol induced hepatic H19 expression
by focusing on two major pathways, epigenetic regulation via DNA methylation and transcriptional regulation
by small heterodimer partner (SHP) and Early Growth Response 1 (EGR1). We will also employ our unique
mouse models, H19 maternal specific knockout (H19Mat+/-) and liver specific H19 DNA methylation domain
(DMD) knockout (H19DMDHep-/-) mice, to explore how loss of H19 function effects the hepatic phenotypes. In
specific aim#2, we will determine the molecular mechanism of how H19 mediates alcohol-induced liver injury.
We screened the H19 interacted proteins using RNA immunoprecipitation assay and found polypyrimidine tract
binding protein 1 (PTBP1) binds to N-terminal of H19 RNA. PTBP1 is an RNA-binding protein to act primarily
as repressive regulator of precursor mRNA (pre-mRNA) alternative splicing. We also found alcohol and H19
reduced PTBP1 expression levels and increased alternative splicing events. Therefore, we will determine the
effect of PTBP1 deficiency on hepatic phenotypes in ethanol-fed mice using our newly generated PTBP1 liver
specific knock out (Ptbp1Hep-/-) mice. Additionally, we identified that H19-PTBP1 axis mediates the splicing of
its novel target gene betaine and homocysteine methyltransferase (BHMT), which was a critical enzyme in the
methionine metabolism pathway. The splicing process led to a decrease in the BHMT protein coding variant
and the reduction in BHMT protein expression led to a dysregulation of methionine metabolism, which
contributed to alcohol induced liver injury. We will perform several mechanistic studies to determine the role of
H19-PTBP1 axis in mediating BHMT alternate splicing. Taken together, we have developed animal and
cellular models to mechanistically study both up and downstream pathways of H19-mediated ALD
pathogenesis. This proposal is of significance and it may lead to potential therapeutic interventions by
targeting H19-PTBP1-BHMT pathway in patients with ALD.

## Key facts

- **NIH application ID:** 10907785
- **Project number:** 5R01AA030993-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Zhihong Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $400,881
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907785

## Citation

> US National Institutes of Health, RePORTER application 10907785, Long Noncoding RNA H19 Mediating Alternative Splicing in ALD Pathogenesis (5R01AA030993-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10907785. Licensed CC0.

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