In summary our results support

In summary, our results support the model that the histone demethylase KDM5 is a critical host transcriptional regulator that maintains immune homeostasis and is responsible for preservation of the normal commensal microbial community structure and behavior. Neurodevelopmental disorders such as ID and ASD present an enormous challenge to affected individuals, their families, and society (Koemans et al., 2017). Our research suggests that direct modification of the gut microbiome can serve as a clinical therapeutic approach for ID and ASD patients with aberrant IMD signaling.
STAR★Methods
Acknowledgments This work was supported by National Natural Science Foundation of China (NSFC) grants 81671983 and 81871628, Natural Science Funding BK20161572 from Jiangsu province of China and starting package from NJMU (X. Liu), Young Scientist Funding BK20161025 from Jiangsu province of China (Q.L. and J.W.), Lawrence Berkeley National Laboratory Directed Research and Development (LDRD) program funding under the Microbes to Biomes (M2B) initiative under contract DE AC02-05CH11231 in the USA (J.-H.M., A.M.S., and S.E.C.), National Institutes of Health (NIH, USA) grant R01GM112783 (J.S.), and National Natural Science Foundation of China (NSFC) grant 31671311 (J.-H.C.). The authors thank X. Liu lab members, reviewers’ suggestions, and the Tsinghua Fly Center.
Eukaryotic DNA is packed in a complex composed of RNA and proteins known as chromatin. The fundamental unit of this complex is the nucleosome, which is composed of 147 bp of DNA wrapped in 1.67 superhelical turns around the octameric histone core (composed of one pair each of histones H2A, H2B, H3, and H4). The DNA structure in get up leads to a five- to 10-fold DNA compaction . These compact structures negatively affect gene expression and are modulated by several mechanisms, including histone posttranslational modifications such as the methylation of lysine and arginine residues, acetylation, the phosphorylation of serine and threonine, ADP-ribosylation, and the ubiquitination and SUMOylation of lysines. These modifications occur mainly at the histone N-terminal tail and promote either chromatin relaxation or compaction into a heterochromatin structure, affecting chromatin architecture and therefore gene transcription . One of the most-studied histone modifications is acetylation, which is controlled by acetyl transferases and deacetylases, suggesting that acetylation is a dynamic histone mark . Lysine methylation is another prominently studied covalent histone modification. This histone mark can be recognized by at least four protein motifs: the chromodomain, the plant homeodomain zinc finger PHD, the Tudor domain, and the WD40-repeat domain , , . Proteins that contain these motifs are recruited by specific methylated lysines. However, the mechanism becomes more complex because lysine residues can be mono-, di-, or trimethylated, and the binding affinity of a protein for a particular modification might be affected by an adjacent modification , . Histone lysine and arginine methylation were believed to be stable and irreversible modifications . However, approximately 30 enzymes capable of removing this covalent modification have been discovered to date. The search for histone demethylases began in the 1960s, when an enzyme that could remove a methyl group from mono- and dimethylated lysine residues was reported . Years later, the same research group partially purified a protein that had histone demethylase function , ; nevertheless, the molecular identity of this enzyme was not fully known for several decades. Not until 2004 was the first histone demethylase—lysine-specific demethylase 1 (LSD1), later renamed lysine (K) demethylase 1 (KDM1)—identified and characterized . This enzyme can remove the methyl groups from lysines 4 and 9 of the histone (H3K4me2/1 and H3K9me2/1, respectively), suggesting that this protein plays a role in the dynamic structure of chromatin and transcription , . KDM1 belongs to the oxidase family that includes enzymes that can demethylate mono- and dimethylated residues using flavin adenine dinucleotide (FAD) as an electron acceptor , . The oxygenase family, also known as the Fe(II) oxygenases, can demethylate mono-, di-, and trimethylated residues; this type of enzyme uses diatomic oxygen and α-oxoglutarate as cosubstrates , , , . Lysine (K)-specific demethylase 4A (KDM4A, also known as JMJD2A, JHDM3A, and KIA0677) is categorized as a member of the Fe(II) oxygenase family.