KDM5C

Official Full Name

lysine demethylase 5C

Organism

Homo sapiens

GeneID

8242

Background

This gene is a member of the SMCY homolog family and encodes a protein with one ARID domain, one JmjC domain, one JmjN domain and two PHD-type zinc fingers. The DNA-binding motifs suggest this protein is involved in the regulation of transcription and chromatin remodeling. Mutations in this gene have been associated with X-linked cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

Synonyms

MRXJ; SMCX; MRX13; MRXSJ; XE169; MRXSCJ; JARID1C; DXS1272E;

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Detailed Information

Recent Research

The KDM5C protein contains 1560 amino acids and is a member of the SMCY homolog family. KDM5C protein specifically reverses the trimethylation and dimethylation of Lys4 of histone H3 (H3K4), helps maintain the homeostasis of histone H3K4 ethylation status, and is also in enhancer and core promoters. It is a multifunctional protein containing highly conserved domains including ARID / Bright, JmjN, JmjC, C5HC2 zinc fingers and two PHD zinc finger domains. The different domains of this protein play different key roles. Moreover, these domains only have specific functionality or are used with other KDM5C domains. The ARID (AT-rich interaction domain) of KDM5C is a DNA-binding domain based on the helix-turn-helix motif, which is highly conserved among all eukaryotic proteins and plays a important role in development, tissue-specific gene expression and cell growth regulation. Another domain, JmjC, catalyzes the demethylation of H3K4me3 to H3K4me1. The JmjN domain and its interaction with the JmjC catalytic domain are important for KDM5C function. The N-terminal PHD zinc finger is a histone methyl-lysine binding motif and shows preferential binding to histone H3K9me3.

KDM5C Figure 1. KDM5C protein domains.

KDM5C is highly expressed in human brain and skeletal muscle tissues, and human KDM5C is involved in the inhibition of specific neuronal genes. In the mouse brain, kdm5c is widely expressed in areas associated with cognitive and emotional behavior, including the prefrontal cortex, hippocampus, and amygdala. KDM5C knockout mice exhibited abnormal social behavior, including aggression and impaired learning and memory. In addition, KDM5C escaped X-inactivation in both mice and humans. In zebrafsh, kdm5c homologs were knocked out to induce brain pattern defects and neuronal cell death, while small interfering RNA (siRNA)-mediated kdm5c knockdown disrupted dendritic morphogenesis in primary rat granule neurons.

KDM5C plays an important role in neural crest migration and eye formation during vertebrate development. In the present study, the functional importance of KDM5C in the embryogenesis of Xenopus laevis was confirmed, and the spatiotemporal expression of KDM5C indicated that it is the maternal gene. The importance of demethylase in neural crest migration and eye development was also confirmed. In addition, knockdown of KDM5C leads to inhibition of neural crest migration and defects in eye development. At the same time, transcriptome analysis of KDM5C MO-injected embryos indicated that KDM5C is critical for morphogenesis of anatomical structures and organogenesis during Xenopus embryo development.

In the current study, KDM5C was overexpressed in gastric cancer cell lines and gastric cancer tissues, but not in normal gastric tissues. Ectopic expression of KDM5C significantly increased the proliferation and invasion of gastric cancer cells. In contrast, RNA interference in gastric cancer cells targeting KDM5C significantly reduced cell proliferation and invasion potential. Furthermore, the expression of p53 is regulated by KDM5C. Cells with KDM5C overexpression showed significantly reduced p53 expression, whereas silencing of KDM5C expression significantly increased p53 expression at messenger RNA and protein levels. Inhibition of p53 by small interfering RNA reversed the proliferation and invasion induced by shKDM5C. Together, these results suggest that KDM5C plays a role in gastric cancer cell proliferation and invasion, which may be partially related to p53 expression.

References:

Yunhui P , et al. Mutations in the KDM5C ARID Domain and Their Plausible Association with Syndromic Claes-Jensen-Type Disease. International Journal of Molecular Sciences, 2015, 16(11):27270-27287.
Scandaglia M , et al. Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons[J]. Cell Reports, 2017, 21(1):47-59.
Kim Y , Jeong Y , Kwon K , et al. Physiological effects of KDM5C on neural crest migration and eye formation during vertebrate development. Epigenetics & Chromatin, 2018, 11(1).
Rondinelli B , et al. H3K4me3 demethylation by the histone demethylase KDM5C/JARID1C promotes DNA replication origin firing. Nucleic Acids Research, 2015, 43(5):2560-2574.

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