The Histone Demethylase KDM5b/JARID1b Plays a Role in Cell Fate Decisions by Blocking Terminal Differentiation

Abstract

The histone demethylase lysine demethylase 5b (KDM5b) specifically demethylates lysine 4 of histone H3 (meH3K4), thereby repressing gene transcription. KDM5b regulates cell cycle control genes in cancer and is expressed in the early epiblast. This suggests that KDM5b plays a developmental role by maintaining uncommitted progenitors. Here we show that transient overexpression of KDM5b in embryonic stem cells decreases the expression of at least three different modulators of cell fate decisions, Egr1, p27 KIP1 , and BMI1, by demethylation of their promoters. Constitutively increased KDM5b expression results in an increased mitotic rate and a decreased global 3meH3K4 but no change in cell identity. Results of two separate differentiation assays, neural differentiation and embryoid body EB (EB) formation, showed that KDM5b reduced the terminally differentiated cells and increased proliferating progenitors. These were achieved by two mechanisms, blocking of the upregulation of cell lineage markers and maintenance of cyclins, that allowed cells to escape differentiation and remain uncommitted. Additionally, EBs maintain high levels of Oct4 and Nanog and can be dissociated to reestablish highly proliferative cultures. The persistence of uncommitted progenitors may be due to the direct regulation of the Tcf/Lef family member mTcf3/hTcf7L1, an upstream regulator of Nanog expression. These findings demonstrate a role for KDM5b in the choice between proliferation and differentiation during development.Transcriptional control is a dynamic process, during which several different histone residues are modified to change RNA polymerase's ability to access the transcriptional start site (19,42). A key component in this process is the methylation of histone H3 lysine 4 (H3K4). Methylation of H3K4 is a key regulator of RNA polymerase binding to active genes (41) and of transcription factor binding within promoter elements (43). The ability of this epigenetic mark to control multiple points in transcription suggests that modulation of H3K4 methylation plays a role in both the activation and the repression of genes.A key aspect of H3K4 methylation is how this epigenetic mark is removed, thereby reducing RNA polymerase's localization to the specific genes. This loss of methyl H3K4

Impaired removal of H3K4 methylation affects cell fate determination and gene transcription

“…The biological functions of the KDM5 members have been studied by analyzing the phenotypes of knockout animals (Albert et al, 2013;Blair et al, 2011;Catchpole et al, 2011;Dey et al, 2008;Iwase et al, 2016;Schmitz et al, 2011) and the results support a role of the KDM5 family members in cell fate determination and differentiation. However, our understanding of the molecular mechanisms behind the observed phenotypes is limited in part by the functional redundancy of the KDM5 family members.…”

“…H3K4me3 level has been correlated to gene expression (Ruthenburg et al, 2007) and, accordingly, loss or downregulation of KDM5 members has been associated with aberrant transcription, albeit the effect is often limited to minor gene expression changes (Albert et al, 2013;Alvares et al, 2014;Christensen et al, 2007;Dey et al, 2008;Iwase et al, 2007Iwase et al, , 2016Schmitz et al, 2011;Tahiliani et al, 2007). As the contribution of RBR-2 to transcriptional control at a global level has not been assessed, we analyzed the transcriptome of rbr-2(tm3141) worms by RNA sequencing (RNA-seq).…”

Physical and Functional Interactions between the Histone H3K4 Demethylase KDM5A and the Nucleosome Remodeling and Deacetylase (NuRD) Complex

“…KDM5A (also known as RBP2 or JARID1A) was first identified as a factor that interacts with the retinoblastoma gene product (RB) (1), and it has been shown to be involved in diverse biological processes such as cellular differentiation (2,3), senescence (4,5), tumorigenesis (6 -8), circadian oscillation (9), and mitochondrial biogenesis (10). KDM5A is a member of the four KDM5 protein family, which also includes KDM5B (PLU-1/ JARID1B), KDM5C (SMCX/JARID1C), and KDM5D (SMCY/ JARID1D), all of which are associated with development and disease (11)(12)(13)(14)(15)(16). Although mammals have four KDM5 family members, other organisms have only one homologue; the homologues in Drosophila (LID) and in Caenorhabditis elegans (RBR-2) also play critical roles in developmental processes (17)(18)(19)(20)(21).…”

Extended Self-Renewal and Accelerated Reprogramming in the Absence of Kdm5b

“…Kdm5b is mainly expressed during development and in adult tissues, such as testis, thymus, brain, spleen, and eye (21,22). Kdm5b is also highly expressed in stem cells, including ES cells (23)(24)(25), neural progenitors (23,24), trophoblast stem (TS) cells (26), and blood lineages (27).…”