KDM1A maintains genome-wide homeostasis of transcriptional enhancers.

Transcriptional enhancers enable exquisite spatiotemporal control of gene expression in metazoans. Enrichment of monomethylation of histone H3 lysine 4 (H3K4me1) is a major chromatin signature of transcriptional enhancers. Lysine (K)-specific demethylase 1A (KDM1A, also known as LSD1), an H3K4me2/me1 demethylase, inactivates stem-cell enhancers during the differentiation of mouse embryonic stem cells (mESCs). However, its role in undifferentiated mESCs remains obscure. Here, we show that KDM1A actively maintains the optimal enhancer status in both undifferentiated and lineage-committed cells. KDM1A occupies a majority of enhancers in undifferentiated mESCs. KDM1A levels at enhancers exhibit clear positive correlations with its substrate H3K4me2, H3K27ac, and transcription at enhancers. In Kdm1a-deficient mESCs, a large fraction of these enhancers gains additional H3K4 methylation, which is accompanied by increases in H3K27 acetylation and increased expression of both enhancer RNAs (eRNAs) and target genes. In postmitotic neurons, loss of KDM1A leads to premature activation of neuronal activity-dependent enhancers and genes. Taken together, these results suggest that KDM1A is a versatile regulator of enhancers and acts as a rheostat to maintain optimal enhancer activity by counterbalancing H3K4 methylation at enhancers.

Alcohol-specific transcriptional dynamics of memory reconsolidation and relapse.

Relapse, a critical issue in alcohol addiction, can be attenuated by disruption of alcohol-associated memories. Memories are thought to temporarily destabilize upon retrieval during the reconsolidation process. Here, we provide evidence for unique transcriptional dynamics underpinning alcohol memory reconsolidation. Using a mouse place-conditioning procedure, we show that alcohol-memory retrieval increases the mRNA expression of immediate-early genes in the dorsal hippocampus and medial prefrontal cortex, and that alcohol seeking is abolished by post-retrieval non-specific inhibition of gene transcription, or by downregulating ARC expression using antisense-oligodeoxynucleotides. However, since retrieval of memories for a natural reward (sucrose) also increased the same immediate-early gene expression, we explored for alcohol-specific transcriptional changes using RNA-sequencing. We revealed a unique transcriptional fingerprint activated by alcohol memories, as the expression of this set of plasticity-related genes was not altered by sucrose-memory retrieval. Our results suggest that alcohol memories may activate two parallel transcription programs: one is involved in memory reconsolidation in general, and another is specifically activated during alcohol-memory processing.

Activation of Xist by an evolutionarily conserved function of KDM5C demethylase.

XX female and XY male therian mammals equalize X-linked gene expression through the mitotically-stable transcriptional inactivation of one of the two X chromosomes in female somatic cells. Here, we describe an essential function of the X-linked homolog of an ancestral X-Y gene pair, Kdm5c-Kdm5d, in the expression of Xist lncRNA, which is required for stable X-inactivation. Ablation of Kdm5c function in females results in a significant reduction in Xist RNA expression. Kdm5c encodes a demethylase that enhances Xist expression by converting histone H3K4me2/3 modifications into H3K4me1. Ectopic expression of mouse and human KDM5C, but not the Y-linked homolog KDM5D, induces Xist in male mouse embryonic stem cells (mESCs). Similarly, marsupial (opossum) Kdm5c but not Kdm5d also upregulates Xist in male mESCs, despite marsupials lacking Xist, suggesting that the KDM5C function that activates Xist in eutherians is strongly conserved and predates the divergence of eutherian and metatherian mammals. In support, prototherian (platypus) Kdm5c also induces Xist in male mESCs. Together, our data suggest that eutherian mammals co-opted the ancestral demethylase KDM5C during sex chromosome evolution to upregulate Xist for the female-specific induction of X-inactivation.

Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation.

Histone H3 lysine 4 methylation (H3K4me) is extensively regulated by numerous writer and eraser enzymes in mammals. Nine H3K4me enzymes are associated with neurodevelopmental disorders to date, indicating their important roles in the brain. However, interplay among H3K4me enzymes during brain development remains largely unknown. Here, we show functional interactions of a writer-eraser duo, KMT2A and KDM5C, which are responsible for Wiedemann-Steiner Syndrome (WDSTS), and mental retardation X-linked syndromic Claes-Jensen type (MRXSCJ), respectively. Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression. Double mutation of Kmt2a and Kdm5c clearly reversed dendritic morphology, key behavioral traits including aggression, and partially corrected altered transcriptomes and H3K4me landscapes. Thus, our study uncovers common yet mutually suppressive aspects of the WDSTS and MRXSCJ models and provides a proof of principle for balancing a single writer-eraser pair to ameliorate their associated disorders.

RAI1 Regulates Activity-Dependent Nascent Transcription and Synaptic Scaling.

Long-lasting forms of synaptic plasticity such as synaptic scaling are critically dependent on transcription. Activity-dependent transcriptional dynamics in neurons, however, remain incompletely characterized because most previous efforts relied on measurement of steady-state mRNAs. Here, we use nascent RNA sequencing to profile transcriptional dynamics of primary neuron cultures undergoing network activity shifts. We find pervasive transcriptional changes, in which ∼45% of expressed genes respond to network activity shifts. We further link retinoic acid-induced 1 (RAI1), the Smith-Magenis syndrome gene, to the transcriptional program driven by reduced network activity. Remarkable agreement among nascent transcriptomes, dynamic chromatin occupancy of RAI1, and electrophysiological properties of Rai1-deficient neurons demonstrates the essential roles of RAI1 in suppressing synaptic upscaling in the naive network, while promoting upscaling triggered by activity silencing. These results highlight the utility of bona fide transcription profiling to discover mechanisms of activity-dependent chromatin remodeling that underlie normal and pathological synaptic plasticity.

Author Correction: Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Yin-yang actions of histone methylation regulatory complexes in the brain.

Dysregulation of histone methylation has emerged as a major driver of neurodevelopmental disorders including intellectual disabilities and autism spectrum disorders. Histone methyl writer and eraser enzymes generally act within multisubunit complexes rather than in isolation. However, it remains largely elusive how such complexes cooperate to achieve the precise spatiotemporal gene expression in the developing brain. Histone H3K4 methylation (H3K4me) is a chromatin signature associated with active gene-regulatory elements. We review a body of literature that supports a model in which the RAI1-containing H3K4me writer complex counterbalances the LSD1-containing H3K4me eraser complex to ensure normal brain development. This model predicts H3K4me as the nexus of previously unrelated neurodevelopmental disorders.

Análisis de la aptitud aeróbica en jóvenes fumadores aparentemente sanos / Analysis of aerobic fitness in apparently healthy young smokers

Introducción y objetivo: Desde el punto de vista etiológico, el hábito del tabaquismo se asocia con diversas enfermedades del sistema respiratorio, hecho que ocasiona una disminución acelerada de la función ventilatoria y la condición física. Sin embargo, esta relación ha sido poco explorada en población militar. Por tanto, el objetivo de este estudio fue examinar la aptitud aeróbica en hombres jóvenes fumadores, aparentemente sanos, pertenecientes a la Escuela de Cadetes José María Córdova. Materiales y métodos: Estudio observacional, descriptivo y transversal en 43 hombres militares aparentemente sanos; 21 fumadores activos (12 meses de exposición) y 22 no fumadores, con edad promedio de 19 ± 1,1 años. La aptitud aeróbica fue estimada mediante el test de Course-Navette (test de Leger), como indicador del consumo de oxígeno máximo indirecto (VO2). Se analizó la respuesta cronotrópica en ambos grupos. Resultados: Se observaron menores valores en la aptitud aeróbica en el grupo de fumadores frente al grupo de no fumadores (44,1 ± 6,6 mL/kg-1/min-1vs. 56,6 ± 3,5 mL/kg-1/min-1; p = 0,001). Asimismo, el grupo de no fumadores presentó mayor respuesta cronotrópica respecto al grupo de fumadores (167 ± 18 lpm vs. 155 ± 20 lpm; p = 0,05). Conclusiones: La aptitud aeróbica en jóvenes fumadores militares fue significativamente menor que en el grupo de no fumadores. Su identificación temprana podría traer beneficios en la prevención de enfermedades respiratorias, que actualmente cursan con carácter de epidemia en Colombia.

Background and objective: The habit of smoking is etiologically associated with different diseases of the respiratory system. It causes an accelerated decline of the ventilatory function and fitness. However, this relationship has been little explored in military population. Therefore, the aim of this study was to examine the aerobic fitness in young male smokers, apparently healthy belonging to the Cadet School José María Córdova. Materials and methods: An observational, descriptive and transversal study was performed. 43 military subjects, apparently healthy, participated in the study: 21 participants were active smokers (12 months of exposition), and 22 subjects were no-smokers; mean age 19 ± 1.1 years. Aerobic fitness was calculated using the Course Navette test (Leger's test), as an indirect indicator of the maximal oxygen intake (VO2max). Chronotropic response was analyzed in both groups. Results: Lower values of aerobic fitness were found in the smokers in relation to the non-smokers (44.1 ± 6.6 mL·kg-1·min-1vs. 56.6 ± 3.5 mL·kg-1·min-1; P = .0001). Non-smokers group showed a higher chronotropic response against the S group (167 ± 18 bpm vs. 155 ± 20 bpm; P = .05). Conclusion: Aerobic fitness in young military smokers was significantly lower than in the non-smokers group. Its early identification could bring benefits in the prevention of respiratory diseases, which are currently present in Colombia and are qualify as epidemic.