Uty-KO Mouse

Uty, also known as KDM6C, is a homologue of the X-chromosome-located KDM6A (UTX) gene on the Y chromosome. It encodes a lysine demethylase that acts on trimethylated lysine at position 27 in histone 3, removing transcriptional repressive marks from histones in the nucleus. Uty is involved in important biological processes such as metabolism, development, and is associated with epigenetic regulation [1,3,5].

In gene knockout studies, female mice with homozygous deletion of Kdm6a do not survive, but hemizygous males are viable, suggesting Uty compensates for the loss of Kdm6a [1]. In male mice, knockdown of Uty led to more severe pulmonary hypertension, with increased expression of proinflammatory chemokines Cxcl9 and Cxcl10, which trigger endothelial cell death and PH [2]. Disruption of Uty in hematopoietic cells in male mice mimicked the profibrotic attributes of Y chromosome loss in heart failure, increasing the propensity of monocytes and macrophages to differentiate into profibrotic macrophages [4].

In conclusion, Uty plays crucial roles in metabolism and development, and its function is revealed through gene-knockout mouse models. These models show its significance in diseases like pulmonary hypertension and heart failure, highlighting its potential as a therapeutic target in understanding and treating these conditions.

References:

1. Gažová, Iveta, Lengeling, Andreas, Summers, Kim M. 2019. Lysine demethylases KDM6A and UTY: The X and Y of histone demethylation. In Molecular genetics and metabolism, 127, 31-44. doi:10.1016/j.ymgme.2019.04.012. https://pubmed.ncbi.nlm.nih.gov/31097364/

2. Cunningham, Christine M, Li, Min, Ruffenach, Gregoire, Arnold, Arthur P, Eghbali, Mansoureh. . Y-Chromosome Gene, Uty, Protects Against Pulmonary Hypertension by Reducing Proinflammatory Chemokines. In American journal of respiratory and critical care medicine, 206, 186-196. doi:10.1164/rccm.202110-2309OC. https://pubmed.ncbi.nlm.nih.gov/35504005/

3. Tran, Nhien, Broun, Aaron, Ge, Kai. 2020. Lysine Demethylase KDM6A in Differentiation, Development, and Cancer. In Molecular and cellular biology, 40, . doi:10.1128/MCB.00341-20. https://pubmed.ncbi.nlm.nih.gov/32817139/

4. Horitani, Keita, Chavkin, Nicholas W, Arai, Yohei, Sano, Soichi, Walsh, Kenneth. 2024. Disruption of the Uty epigenetic regulator locus in hematopoietic cells phenocopies the profibrotic attributes of Y chromosome loss in heart failure. In Nature cardiovascular research, 3, 343-355. doi:10.1038/s44161-024-00441-z. https://pubmed.ncbi.nlm.nih.gov/39183958/

5. Vogt, Peter H, Zimmer, Jutta, Bender, Ulrike, Strowitzki, Thomas. 2021. AZFa candidate gene UTY and its X homologue UTX are expressed in human germ cells. In Reproduction & fertility, 2, 151-160. doi:10.1530/RAF-20-0049. https://pubmed.ncbi.nlm.nih.gov/35128450/