# Human LincRNAs in Macrophage Biology and Related Cardiometabolic Diseases

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $664,674

## Abstract

Most human complex trait genetic signals lie in intergenic regions, implicating regulatory elements, including
long intergenic non-coding RNAs (lincRNAs). These are typically not conserved in mouse and often cell-specific,
raising challenges to mechanistic study but also providing a major opportunity for advances in human health and
disease. Here, we embrace this challenge in interrogation of three non-conserved lincRNAs that we prioritized
from deep RNAseq and preliminary functional studies in human macrophages. Macrophage activation to diverse
functional states plays a central role in cardiometabolic diseases (CMD). We hypothesize that human lincRNAs
modulate macrophage inflammatory and metabolic functions that impact complex CMD. To date regulatory
effects of a few lincRNAs on macrophage biology have been reported, but the vast majority of human
macrophage lincRNAs has yet to be studied. Through RNAseq of primary human monocyte-derived
macrophages (HMDM), we identified 2,776 multi-exon lincRNAs of which >80% are not annotated in mouse.
Based on (i) modulation during macrophage activation, (ii) overlap with genetic signals for CMD, (iii) macrophage
enrichment and abundance, (iv) ChIP-seq binding of CEBPa and PU.1 proteins, and (v) similar expression
pattern in human induced pluripotent stem cells (hiPSC) derived macrophages (IPSDM), we selected a set of 22
lincRNAs for validation and preliminary translation. From these, we focus here on three lincRNAs, not expressed
in mouse macrophages, that have preliminary evidence of human macrophage functions. RP11-10J5.1 is
markedly induced during inflammatory M1 activation, has increased expression in human atherosclerosis and
attenuates iNOS expression and apoptosis (Aim 1). In contrast, RP11-184M15.1 is highly induced during M2
macrophage activation and modulates M2 phenotype (Aim 2). Finally, RP11-472N13.3 associates with central
human obesity and attenuates macrophage IFNg signaling (Aim 3). Because large-scale genetic manipulation
in primary human macrophages is limiting, we propose CRISPR/Cas9 gene-editing in IPSDM to pursue
functional genomic interrogations of these CMD-relevant lincRNAs. Key findings will be corroborated by
knockdown (KD) and overexpression (OE) of lincRNAs in HMDM. Localization, miR binding and protein
interactions will be defined by RNA fluorescence in situ hybridization, MS2-tagged RNA affinity purification,
confirmed with QPCR, and pull-down with biotinylated lincRNA probes coupled to mass-spectrometry and with
RNA immunoprecipitation. KD and OE of interacting partners will test lincRNAs functional roles via specific miR
or proteins target(s). Human disease relevance will be determined by localizing lincRNAs to macrophages in
coronary atherosclerosis and visceral adipose and through interrogation of lincRNA cis-regulatory variants,
identified via macrophage allele specific expression, in CMD genetic datasets.

## Key facts

- **NIH application ID:** 9983136
- **Project number:** 5R01HL132561-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Muredach P Reilly
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $664,674
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983136

## Citation

> US National Institutes of Health, RePORTER application 9983136, Human LincRNAs in Macrophage Biology and Related Cardiometabolic Diseases (5R01HL132561-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9983136. Licensed CC0.

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