Methylation across the central dogma in health and diseases: new therapeutic strategies

The proper transfer of genetic information from DNA to RNA to protein is essential for cell-fate control,development,and health.Methylation of DNA,RNAs,histones,and non-histone proteins is a reversible post-synthesis modification that finetunes gene expression and function in diverse physiological processes.Aberrant methylation caused by genetic mutations or environmental stimuli promotes various diseases and accelerates aging,necessitating the development of therapies to correct the disease-driver methylation imbalance.In this Review,we summarize the operating system of methylation across the central dogma,which includes writers,erasers,readers,and reader-independent outputs.We then discuss how dysregulation of the system contributes to neurological disorders,cancer,and aging.Current small-molecule compounds that target the modifiers show modest success in certain cancers.The methylome-wide action and lack of specificity lead to undesirable biological effects and cytotoxicity,limiting their therapeutic application,especially for diseases with a monogenic cause or different directions of methylation changes.Emerging tools capable of site-specific methylation manipulation hold great promise to solve this dilemma.With the refinement of delivery vehicles,these new tools are well positioned to advance the basic research and clinical translation of the methylation field.

Bombyx mori U-shaped regulates the melanization cascade and immune response via binding with the Lozenge protein

Zinc finger protein,an important transcription factor,regulates gene expression associated with various physiological and pathological processes.U-shaped,belong to the Friend of GATA(FOG)transcription factor,plays a crucial role in hematopoiesis by interacting with the GATA transcription factor as a co-factor.However,little is known about its functions in insects.In the present study,a U-shaped cDNA was identified and characterized from the silkworm Bombyx mori and its potential roles in innate immunity investigated.The predicted silkworm U-shaped amino acid sequence contained a classical nuclear localization signal(NLS)motif“GESSPKRRRR”at position 45CU459,and arginine residues at position 456 and 478 are the critical sites of the NLS.U-shaped mRNA was detected in all tested tissues of the B.mori;however,the highest levels were found in the hemocytes.U-shaped mRNA expression levels were upregulated in the hemocyte after the Escherichia coli and Staphylococcus aureus challenge.Furthermore,U-shaped knockdown significantly reduced the melanization process and suppressed the expression of melanization-associated genes,including PPO1,PPO2,PPAE and BAEE.In addition,U-shaped interacts with Lozenge protein to regulate the innate immune response of the insect.Our results revealed that U-shaped binds directly to Lozenge protein to modulate the melanization process and innate immune responses in silkworm.

Integrin β2 and β3:Two plasmatocyte markers deepen our understanding of the development of plasmatocytes in the silkworm Bombyx mori

Insect hemocytes play important biological roles at developmental stages,metamorphosis,and innate immunity.As one of the most abundant cell types,plasmatocytes can participate in various innate immune responses,especially in encapsulation and node formation.Here,2 molecular markers of plasmatocytes,consisting of integrinβ2 andβ3,were identified and used to understand the development of plasmatocytes.Plasmatocytes are widely distributed in the hematopoietic system,including circulating hemolymph and hematopoietic organs(HPOs).HPOs constantly release plasmatocytes with high proliferative activity in vitro;removal of HPOs leads to a dramatic reduction in the circulating plasmatocytes,and the remaining plasmatocytes gradually lose their ability to proliferate in vivo.Our results demonstrated that the release of plasmatocytes from HPOs is regulated by insulin-mediated signals and their downstream pathways,including PI3K/Akt and MAPK/Erk signals.The insulin/PI3K/Akt signaling pathway can significantly irritate the hematopoiesis,and its inhibitor LY294002 could inhibit the hemocytes discharged from HPOs.While the insulin/MAPK/Erk signaling pathway plays a negative regulatory role,inhibiting its activity with U0126 can markedly promote the discharge of plasmatocytes from HPOs.Our results indicate that the circulating plasmatocytes are mainly generated and discharged by HPOs.This process is co-regulated by the PI3K/Akt and MAPK/Erk signals in an antagonistic manner to adjust the dynamic balance of the hemocytes.These findings can enhance our understanding of insect hematopoiesis.

Hedgehog promotes cell proliferation in the midgut of silkworm,Bombyx mori

The Hedgehog(Hh)signaling pathway is one o f the major regulators of embryonic development and tissue homeostasis in multicellular organisms.However,the role of this pathway in the silkworm,especially in the silkworm midgut,remains poorly understood.Here,we report that Bombyx mori Hedgehog(BmHh)is expressed in most tissues of silkworm larvae and that its functions are well-conserved throughout evolution.We further demonstrate that the messenger RNA o f four Hh signaling components,BmHh ligand,BmPtch receptor,signal transducer BmSmo and transcription factor BmCi,are all upregulated following Escherichia coli or Bacillus thuringiensis infection,indicating the activation o f the Hh pathway.Simultaneously,midgut cell proliferation is strongly promoted.Conversely,the repression of Hh signal transduction with double-stranded RNA or cyclopamine inhibits the expression o f BmHh and BmCi and reduces cell proliferation.Overall,these findings provide new insights into the Hh signaling pathway in the silkworm,B.mori.