# Genetic and hypoxic control of a lncRNA axis orchestrates endothelial reprogramming in pulmonary hypertension

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $686,433

## Abstract

Background and Hypothesis: Pulmonary hypertension (PH) is a deadly disease, where Group 1 PAH and
Group 3 PH are driven by hypoxia, HIF-2α, and non-coding RNAs. We found that the lncRNA KMT2E-AS1 is
up-regulated in Groups 1/3 PH and is induced by HIF-2α. This lncRNA gene neighbors KMT2E, a gene
controlling histone 3 lysine 4 trimethylation (H3K4me3) and chromatin remodeling. In pulmonary endothelial cells
(ECs), KMT2E-AS1 stabilizes KMT2E to increase H3K4me3, thus driving HIF-2α-specific metabolic and
pathogenic alterations. The G-allele of single nucleotide variant (SNV) rs73184087 within KMT2E is associated
with risk of developing Group 1 PAH (in discovery/validation cohorts and a meta-analysis of 2,181 PAH vs.
10,060 controls). rs73184087 also displays more avid allele (G)-specific association with HIF-2α leading to
induction of this lncRNA-KMT2E pair. A mouse deficient in the conserved lncRNA sequence is protected against
Groups 1/3 PH; this is phenocopied by inhibition of histone methylation in PAH rats. We postulate that the
KMT2E-AS1/KMT2E axis is a central lynchpin in pathogenic reprogramming in ECs, promoting PH. Aim
1) Define the allele-specific role of the KMT2E SNV rs73184087 in controlling HIF-2α-dependent EC
lncRNA-KMT2E expression and PH pathophenotypes. Using ECs derived from genome-edited inducible
pluripotent stem cells (iPSC) as well as primary lung ECs carrying rs73184087 A and G alleles, we will determine
if (G) increases lncRNA-KMT2E by more HIF-2α binding and drives more severe EC phenotypes. We will also
pursue expression quantitative trait loci (eQTL) analysis in blood samples from PAH patients
(discovery/validation cohorts) and PAH lung tissues carrying A and G alleles of rs73184087. Aim 2) Define the
role of this lncRNA-KMT2E axis and H3K4me3 in promoting PH in vivo. We will quantify Groups 1/3 PH
severity in rodents after EC-specific knockdown of this lncRNA vs. lncRNA+KMT2E and after AAV-driven EC-
specific expression of lncRNA vs. lncRNA+KMTE2. We will also determine if MM-589, a specific H3K4me3
inhibitor, reverses PAH in rats. Thus, we aim to determine if lncRNA+KMT2E together are necessary and
sufficient to drive Group 1/3 PH and if PAH is dependent upon H3K4me3 activity, thus offering a new epigenetic
PH therapy. Aim 3) Define the causative role of the G allele of rs73184087 on pulmonary vascular
remodeling and PH in vivo. Culturing human precision cut lung slices, we will determine if the rs73184087 G
allele drives vascular remodeling via regulation of the lncRNA-KMT2E axis and H3K4me3. We have also inserted
the human rs73184087 G vs. A allele in mice and will use these “humanized” mice to study these alleles in vivo.
With these 2 unique platforms, we will determine if the G allele drives HIF-2α-specific EC phenotypes and PH.
Significance: We plan to shift paradigms of lncRNA biology in PH, via defining the links of hypoxia to epigenetics
and metabolism and by introducing new epigenetic therapies. By establishin...

## Key facts

- **NIH application ID:** 10913988
- **Project number:** 5R01HL151228-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Stephen Y Chan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $686,433
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10913988

## Citation

> US National Institutes of Health, RePORTER application 10913988, Genetic and hypoxic control of a lncRNA axis orchestrates endothelial reprogramming in pulmonary hypertension (5R01HL151228-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10913988. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*