Elsevier

Current Opinion in Neurobiology

Volume 59, December 2019, Pages 9-15
Current Opinion in Neurobiology

Histone demethylases in neuronal differentiation, plasticity, and disease

https://doi.org/10.1016/j.conb.2019.02.009Get rights and content

Highlights

  • •

    Neuronal functions of the histone demethylases LSD1, Kdm6b, and Kdm5c.

  • •

    Evidence for potential non-enzymatic functions of the histone demethylases.

  • •

    Summarize neurological disease-associated mutations in HDMs.

For more than 40 years after its discovery, histone methylation was thought to be largely irreversible. However, the first histone demethylase (HDM) was identified in 2004, challenging this notion. Since that time, more than 20 HDMs have been identified and characterized, and many have been shown to have critical roles in organismal development, cell fate, and disease. Here, we highlight some of the recent advances in our understanding of the function of HDMs in the context of neuronal development, plasticity, and disease. We focus, in particular, on molecular genetic studies of LSD1, Kdm6b, and Kdm5c that have elucidated both enzymatic and non-enzymatic gene regulatory functions of these HDMs in neurons.

Introduction

Post-translational modifications to the N-terminal tails of the histone proteins play crucial roles in genome regulation [1]. These modifications (e.g. acetylation, methylation, phosphorylation) are deposited by so-called ‘writer’ enzymes and dynamically removed by the action of ‘eraser’ enzymes. Although histone methylation was long thought to be irreversible due to its chemical stability, the identification of a large group of enzymes with histone demethylase activity challenged this assumption. Histone demethylases (HDMs) can be broadly classified into two families based on their mechanisms of enzymatic action: the two amine oxidase demethylases (LSD1/KDM1A and LSD2/KDM1B) and the much larger Jumonji C domain (JmjC) family, which has more than 20 members [2]. The discovery of such a large set of HDMs, along with the observation of their specificity for the demethylation of distinct residues on the histone tails, immediately raised the possibility that these enzymes dynamically regulate histone methylation-dependent cellular processes. Indeed, HDMs have been found to play crucial roles in development and contribute to pathological processes like cancer and aging.

Neurons are long-lived postmitotic cells that continuously adapt their gene expression programs to the environment; thus, these cells serve as a particularly good substrate for discovering the function of chromatin regulators including HDMs in genome dynamics. Here, we review recent hallmark studies on the functions of HDMs in neurons, focusing in particular on biological and biochemical studies of three of the best studied neuronal HDMs (summarized in Figure 1) that offer new insight into the roles of chromatin regulation in the brain.

Section snippets

LSD1: protein complexes and splicing determine target specificity

Lysine-specific demethylase 1 (LSD1) was the first HDM to be discovered [3] and has been one of the most widely studied. LSD1 was initially characterized as a transcriptional repressor that interacts with the CoREST complex and specifically demethylates the transcriptional activation-associated mark histone H3 mono or dimethylated at lysine 4 (H3K4me1 and H3K4me2) [4]. However, LSD1 was also co-purified with the androgen receptor and was found to act as a coactivator of transcription via its

Kdm6b: relief of polycomb-mediated repression

Kdm6b/Jmjd3 is one of a small family of two HDMs (Kdm6a/Utx is the other HDM) that has specificity for removal of the H3K27me2/3 marks laid down by the polycomb repressive complex. Over the course of neuronal differentiation, Kdm6b is important for removing H3K27me3 in the context of bivalent chromatin marks. Bivalency describes regulatory elements that are associated with both H3K4me3 and H3K27me3, which are histone modifications normally correlated with gene activation and repression,

Kdm5c: mutations in X-linked intellectual disability

As mentioned above, targeted exome sequencing studies are rapidly revealing de novo mutations in a number of chromatin regulators associated with neurodevelopmental disorders including ID and ASD [33,34]. In addition, familial mutations in the H3K4-selective demethylase KDM5C (SMCX/JARID1C) have been identified as one of the more frequent causes of X-linked intellectual disability (XLID) (Figure 2c) [35]. In either case, the genetic association between any chromatin regulator and disease is

Other HDMs in neurodevelopmental disorders

In addition to the HDMs highlighted here, many other HDMs are expressed in neurons [29], and mutations in several of these have been found in neurodevelopmental syndromes, highlighting their importance human brain development. For example, microdeletion of 12a24.31, which is a genomic region that contains both KDM2B and the histone methyltransferases SETD1B, causes an ID syndrome [40], and multiple mutations in the H3K9 demethylase JMJD1C (KDM3C) were found upon targeted resequencing of a set

Concluding remarks

The discovery of HDMs not only opened the door to understanding the roles of dynamic histone methylation but also gave us new genetic tools to explore the mechanisms and consequences of gene regulation in the brain. The identification of disease-associated mutations in HDMs and the study of mouse knockout models have revealed fundamental insights about the biological requirements for these enzymes. Future studies will reveal mechanistic insights about recruitment of HDMs to their target genes,

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Urann Chan for assistance with the figures. This work was supported in part by National Institutes of Health grant 1R01NS098804 (A.E.W.).

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