LSD also contributes to the regulation of specific programs

LSD1 also contributes to the regulation of specific programs of gene expression in postmitotic, fate-committed neurons. Perhaps its most specialized role is in the complex series of epigenetic regulatory events that permit each olfactory sensory neuron to express one and only one of the thousands of possible olfactory receptor genes [11]. To more broadly study the function of LSD1 in the adult brain, Christopher et al. [12] conditionally deleted floxed Kdm1a in adult mice with a tamoxifen-inducible Cre transgene. Loss of LSD1 from the adult brain resulted in widespread neuronal death throughout the cortex and hippocampus. Gene expression analysis showed reactivation of stem cell genes in the hippocampus of LSD1 knockout mice, and bioinformatics, suggested an overall similarity of the knockout gene expression profile to that seen in cases of Alzheimer’s disease and frontotemporal dementia. Whether insults to LSD1 function directly cause neurodegeneration remains unknown; however, these data suggest that continuous expression of LSD1 in the adult brain is required for the maintenance of proper neuronal function. Interestingly, LSD1 has a neuronal-specific splice variant, which comprises about half of all LSD1 in the adult brain and is the predominant form of LSD1 expressed in the early postnatal brain [13]. Referred to as NeuroLSD1 or LSD1n, this variant is characterized by the inclusion of a 12-nucleotide microexon (E8a) that adds just four VX-661 receptor to the enzymatic amine oxidase domain [14]. Nonetheless, variant-specific knockout or knockdown of LSD1n has shown that this small change in the LSD1 sequence has major effects on LSD1 function. The brains of LSD1n knockout mice are hypoexcitable and show decreased seizure susceptibility [15]. LSD1n mutant mice also display impaired spatial learning and memory in the Barnes maze [16] and reduced stress-induced anxiety-like behavior [17]. These behavioral changes correlate with impaired activity-dependent induction of immediate-early genes (IEGs), which have been suggested to play important roles in the cellular and circuit adaptations that underlie learning and memory. How does LSD1n promote IEG induction? Phosphorylation of the LSD1n tetrapeptide has been suggested to inhibit association with CoREST and to block the repressive H3K4 demethylase activity of LSD1 [18]. Given evidence that LSD1n binds to at least some of the same target genes as LSD1, one possibility is that LSD1n functions as a dominant negative, blocking the repressive actions of LSD1 [13]. Alternatively, one group found that LSD1n binds a co-regulatory protein called supervillin, which directs the complex to demethylate H3K9me2, thus promoting gene activation [19]; another group proposed a model in which LSD1n acquires specificity to demethylate H4K20, promoting transcriptional elongation [16].
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, respectively [20]. During the early stages of cell fate commitment, bivalent chromatin is found at promoters of cell-type specific genes that are poised to turn either on or off depending on the fate of the cell. For example, Kdm6b-dependent resolution of bivalency is required for proper activation of Nestin expression in embryonic stem cell-derived neural progenitor cells during commitment to the neuronal lineage [21]. In vivo, conditional knockout or knockdown of Kdm6b impairs neurogenesis in the olfactory bulb (OB) [22], the spinal cord [23], and the retina [24]. These studies have revealed diversity in the action of Kdm6b. In the spinal cord, Kdm6b is bound to a set of gene promoters that are activated during TGFβ-dependent neural differentiation, and it collaborates with Smad3 to induce promoter demethylation and transcriptional activation [23]. By contrast, although Kdm6b is required for the expression of the transcription factor Dlx2 in OB progenitors, it acts by regulating H3K27me3 at a distal enhancer of this gene rather than at the gene promoter [22]. In the retina, although Kdm6b is also pro-differentiation, Kdm6b is expressed most highly in young postmitotic neurons, and loss of Kdm6b function impairs the development of only a subset of retina cell types that undergo developmental loss of H3K27me3 at the Bhlhb4 promoter [24]. Finally, given that substantial developmental loss of H3K27me3 during neural commitment can still occur in the absence of the Kdm6 family [25], it remains important to test which of the functions of Kdm6b in neural differentiation require the action of its histone demethylation function.