The lysine K specific demethylase KDM family is comprised of

The lysine (K)-specific demethylase 4 (KDM4) family is comprised of 4 isoforms, KDM4A to -D, also known as JMJD2A to -D. KDM4A, B, and C encode proteins consisting of a JmjC, a JmjN, two PHD, and two Tudor domains. KDM4D is unique within the KDM4 family in that it has neither PHD nor Tudor domains, therefore it is only half the size of KDM4A-C [19]. Previous studies showed that KDM4D can be swiftly recruited to DNA damage sites in a PARP1-dependent manner and facilitate double-strand break repair in human cells, which ensure efficient repair of DNA lesions to maintain genome stability [20,21]. KDM4D is also a novel cofactor of androgen receptor since it interacts with androgen receptor and stimulates its ability to up-regulate transcription, which plays an indispensable role in prostate cancer [22].
Materials and methods
Results
Discussion Hepatic fibrosis, characterized by HSC activation and excessive production and deposition of extracellular matrix in the liver, serves to disrupt normal liver structure and heralds more severe, irreparable liver pathologies such as hepatic failure and hepatocellular carcinoma. HSCs, the major source of fibrogenesis in the liver, locate in the Disse pace of the normal liver, and are activated into myofibroblasts by chronic stimulation. Once activated, HSCs show enhanced cell proliferation, express excessive α-SMA, and overproduce extracellular matrix. Post-translational regulations in mammals are dictated by the epigenetic mechanism, of which histone modifications constitute a key branch. They can influence KB-R7943 mesylate structure, ultimately leading to gene expression alterations [26]. A series of epigenetic enzymes are actively involved in the addition or removal of covalent modifications, which include acetylation/deacetylation, methylation/demethylation, phosphorylation, ubiquitination, and sumoylation [27,28]. Deregulation of these processes is a hallmark of pathogenesis. The mechanism of epigenetic regulation in hepatic fibrogenesis has not been well elucidated, therefore, studies on the relationship between epigenetic modifications and liver fibrosis will refine our understanding of the fibrotic pathogenesis. The complexity of dynamic regulatory networks in the pathogenesis of liver fibrosis raises the importance of further exploration for novel factors and signaling pathways. Here, we uncovered that KDM4D, a histone demethylase, as a novel epigenetic regulator of HSC activation and thereby modulates hepatic fibrogenesis by altering methylation status of H3K9. KDMs are versatile proteins that modulate multiple cellular processes, such as gene expression regulation, cell differentiation, embryonic stem cell renewal, and tumor development [29]. Our data portray KDM4D as a protein bridging H3K9 demethylation with HSC activation. Using H3K9me2 as a proxy for KDM4D activity is reasonable, as its level is coregulated by both histone methyltransferases and demethylases. Coincidently, the level of both histone H3 methyltransferases and demethylases are upregulated during HSC activation. Given KDM4D is the most abundant histone demethylase whose expression level is much higher than any of the other histone methylase or demethylase, we can say that it is histone demethylases rather than methyltransferases who predominantly contribute to the decline of H3K9me2 and H3K9me3 level during HSC activation. KDM4D consists of evolutionarily conserved JmjN and JmjC domains at its N terminus whereas the overall sequence of its C-terminal region contains no obvious characterized domain [10]. Apart from its well-known regulatory roles in the DNA damage response, KDM4D also stimulates p53-dependent transcriptional activity, which points to a pro-oncogenic implication [30]. In this study, a novel function of KDM4D in liver fibrogenesis was described. We uncovered that the expression of KDM4D greatly increased during trans-differentiation of quiescent HSCs to activated ones, also it was required for collagen contraction and migration capacity of HSCs. The specific change of KDM4D in HSC may represent an epigenetic alteration during fibrogenesis. Further, the severity of established liver fibrosis was alleviated as a result of Kdm4d knockdown in vivo. Kdm4d-deficient mice showed a notable reduction in not only hepatic injury severity. At the same time, Kdm4d depletion caused a significant suppression of crosslinked collagen deposition, which derived from HSC activation.