Histone demethylases in chromatin biology and beyond

Abstract

Histone methylation plays fundamental roles in regulating chromatin-based processes. With the discovery of histone demethylases over a decade ago, it is now clear that histone methylation is dynamically regulated to shape the epigenome and regulate important nuclear processes including transcription, cell cycle control and DNA repair. In addition, recent observations suggest that these enzymes could also have functions beyond their originally proposed role as histone demethylases. In this review, we focus on recent advances in our understanding of the molecular mechanisms that underpin the role of histone demethylases in a wide variety of normal cellular processes.

Keywords: chromatin; demethylase; epigenetics; histone methylation.

Figure 1. Mechanisms regulating targeting and occupancy of histone demethylases on chromatin

(A) Generic targeting mechanisms. Many histone demethylases encode “reader domains”, including PHD, Tudor and TPR domains (left), that bind and read histone modifications found broadly throughout the genome. These interactions function to target histone demethylases to chromatin and regulate their activity. Some histone demethylases interact with chromatin via direct binding to DNA. This is exemplified by the KDM2 histone demethylases that are targeted generically to CpG islands, resulting in localized removal of histone methylation at these sites (middle). Histone demethylases are often found in large multi‐protein complexes, which contain other chromatin‐binding proteins that function to target these enzymes to chromatin (right). (B) Sequence‐specific targeting mechanisms. Histone demethylases in some instances are targeted to specific sites in the genome through interaction with transcription factors (left) or with lncRNAs (right).

Figure 2. Histone demethylases shape chromatin architecture at gene regulatory elements to regulate gene expression

(A) Demethylases actively remove histone methylation to establish new chromatin environments at gene regulatory elements. Removal of repressive modifications, such as H3K27me2/3, helps to create transcriptionally permissive chromatin (top), while removal of transcriptionally permissive modifications, such as H3K4me3, contributes to the formation of more repressive chromatin states (bottom). These processes appear to be particularly important in achieving new gene expression programs during lineage commitment and cellular reprogramming. (B) Histone demethylases play a key role in the maintenance of established chromatin states by preventing the spurious accumulation of alternative histone methylation states. For example, the H3K4me2/3 demethylase KDM5C contributes to the maintenance of enhancer identity by maintaining local H3K4me1 levels.

Figure 3. Histone demethylation is an integrated part of the cell cycle

Several histone demethylases play important roles at defined stages to support normal cell cycle associated processes. For example, they contribute to the establishment of chromatin states that are required for the expression of important cell cycle regulators, DNA replication, segregation of chromosomes, and genomic stability during cell division. Misregulation of these histone demethylases, or their activity, often causes cell cycle arrest and may also lead to genomic instability in cancer.

Figure 4. Emerging functions that are independent of histone demethylation

(A) Histone demethylases have also been demonstrated to remove methyl groups from non‐histone protein substrates to regulate their abundance, stability or activity. (B) Histone demethylases function more generally as 2‐OG oxygenases, catalysing the hydroxylation of various protein and non‐protein substrates, including ribosomal proteins, transcription factors and tRNA. (C) Histone demethylases can possess alternative enzymatic activities. For example, KDM1B functions as an E3 ubiquitin ligase that ubiquitylates OGT leading to its proteasomal degradation. (D) Histone demethylases appear to function as molecular scaffolds, exploiting their chromatin‐binding capacity to recruit other proteins and chromatin remodelling activities.