The lncRNA HOXA11os protects against intestinal inflammation through regulation of mitochondrial function

Liraz Galia ¹ Fiachra Humphries ¹ Tim Vierbuchen ¹ Zhaozhao Jiang ¹ Nolan Santos ¹ John Johnson ² Boris Shklyar ³ Leonel Joannas ^4,5 Nicholas Mustone ¹ Shany Sherman ^7,8 Doyle Ward ^9,10 Jean Marie Houghton ¹¹ Christina E. Baer ¹² Jorge Henao-Mejia ^4,5,6 Kasper Hoebe ² Katherine A. Fitzgerald ¹

¹Program in Innate Immunity, Department of Medicine, Division of Innate Immunity, University of Massachusetts Chan Medical School, USA
²Janssen Pharmaceutical Research and Development, Spring House, USA
³Bioimaging Unit, Faculty of Natural Sciences, University of Haifa, Israel
⁴Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, USA
⁵Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, USA
⁶Division of Protective Immunity, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania, USA
⁷Department of Medicine, Division of Dermatology, University of Massachusetts Chan Medical School, USA
⁸Sackler Faculty of Medicine, Tel Aviv University, Israel
⁹Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, USA
¹⁰Center for Microbiome, University of Massachusetts Chan Medical School, USA
¹¹Division of Gastroenterology, Department of Medicine, University of Massachusetts Chan Medical School, USA
¹²Sanderson Center for Optical Imaging and Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, USA

Ulcerative colitis is a chronic inflammatory disease of the colon with a multifactorial etiology and no definitive cure. Thus, studies to identify new regulatory factors especially those with the potential to restore tissue homeostasis are required. Recent reports have suggested that dysregulated expression of long noncoding RNAs (lncRNAs) is associated with the pathogenesis of ulcerative colitis. Yet, physiological functions of lncRNAs in the pathogenesis of the disease remain to be defined in detail.

In this study we have identified the lncRNA HOXA11os as a key regulator of intestinal homeostasis. Murine HOXA11os and its human ortholog HOXA11AS are highly conserved and specifically expressed in the distal colon. Both HOXA11os and HOXA11AS are highly abundant in the healthy colon and downregulated to an undetectable level in colitis. Mice deficient in HOXA11os were hypersusceptible to intestinal inflammation. Remarkably, localization analysis revealed that HOXA11os was predominantly localized to the mitochondria in cells of the distal colon and is an RNA constituent of the Krebs cycle and mitochondrial oxidative phosphorylation (OXPHOS). Mechanistically, HOXA11os deficient mice displayed impaired mitochondrial function, reduced production in ATP and elevated mitochondrial ROS, rendering HOXA11os deficient mice more susceptible to colitis.

In summary our study has uncovered a new metabolic signaling pathway that bridges cell metabolism and the onset of colitis through expression of the lncRNA HOXA11os. HOXA11os is a constitutive factor of the OXPHOS in the distal colon required for the efficient metabolic function during the resolution of intestinal inflammation.