Nuclear transglutaminase 2 directly regulates expression of cathepsin S in rat cortical neurons

• Published in: The European journal of neuroscience 2018-11, Vol.48 (9), p.3043-3051
• Main Authors: Ji, Changyi, Tang, Maoping, Harrison, Jarreau, Paciorkowski, Alex, Johnson, Gail V. W.
• Format: Article
• Language: English
• Subjects: Animals; Bioinformatics; Cathepsin S; Cathepsins - biosynthesis; Cathepsins - genetics; Cell Survival - physiology; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - metabolism; ChIP‐seq; Chromatin; Deoxyribonucleic acid; DNA; DNA motif; Female; Gene Expression; Humans; Immunoprecipitation; Localization; neuronal survival; Neurons; Neurons - metabolism; Nucleotide sequence; Pregnancy; rat cortical neurons; Rats; TG2; Transglutaminase 2; Transglutaminases - physiology
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.14159

Transglutaminase 2 (TG2) is a protein that modulates neuronal survival processes. Although TG2 is primarily cytosolic, data have suggested the nuclear localization of TG2 is strongly associated with neuronal viability. Depletion of TG2 in neurons results in neurite retraction and loss of viability, which is likely due to a dysregulation in gene expression. To begin to understand how TG2 regulates neuronal gene expression, chromatin immunoprecipitation was performed in neurons with TG2 overexpression. The resulting genomic DNA was recovered and sequenced. Bioinformatics analyses revealed that a signature DNA motif was enriched in the TG2 immunoprecipitated genomic DNA. In particular, this motif strongly mapped to a region proximate to the gene Ctss (cathepsin S). Knockdown of TG2 resulted in a significant increase in cathepsin S expression, which preceded the loss of neuronal viability. This is the first demonstration that TG2 directly associates with genomic DNA and regulates gene expression in neurons. Given that expression of cathepsin S is increased in neurological disease states, our data suggest that TG2 may play a role in promoting neuron health in part by repressing the expression of cathepsin S. Overall these data provide new insights into the function of nuclear TG2 in neurons. The results of this study indicate that TG2 directly associates with genomic DNA and regulates gene expression in neurons, most prominently by facilitating repression. Analysis of the DNA pulled down with TG2 revealed that a signature DNA motif that strongly mapped to a region proximate to the gene Ctss (cathepsin S). Knockdown of TG2 in neurons resulted in a significant increase in cathepsin S expression and increased cell death.