Introduction Post translational modifications to the N termi

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 parthenolide 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.
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 ability to demethylate the repressive marks H3K9me1 and H3K9me2 [5]. The association of LSD1 with distinct protein complexes appears to direct its specificity toward different histone modifications, allowing this single enzyme to have opposing functions in transcriptional regulation in distinct contexts [6]. Mutations that impair the enzymatic activity of LSD1 have been associated with intellectual disability (ID), suggesting the relevance of LSD1’s demethylase function in human brain development (Figure 2a) []. Kdm1a knockout mice die by embryonic day 6.5, precluding the study of brain development in these animals [8]. However, knockdown or inhibition of LSD1 in neuronal progenitors has revealed that it serves as a positive regulator of neuronal differentiation in the developing brain. In cortical progenitors, LSD1 forms a complex with the transcriptional corepressor CoREST and binds to the promoter of Hes1, a transcriptional repressor and key effector of the Notch signaling pathway [9]. Knockdown of LSD1 or CoREST by in utero electroporation leads to an increase in Hes1 expression and reduced expression of its proneural downstream target, the basic helix-loop-helix transcription factor, Ngn2. These data indicate that LSD1 opposes Notch to promote cortical neuronal differentiation. Similar functions for LSD1 were observed in retinal development, where peak LSD1 expression occurs during the period of rod photoreceptor differentiation [10]. Inhibition of LSD1 in cultured retinal explants was shown to increase expression and H3K4me2 deposition on promoters of progenitor-expressed genes, including Hes1, and block induction of terminal rod differentiation markers despite the normal expression of rod photoreceptor transcription factors.