RESUMO
During spermatogenesis, intricate gene expression is coordinately regulated by epigenetic modifiers, which are required for differentiation of spermatogonial stem cells (SSCs) contained among undifferentiated spermatogonia. We have previously found that KMT2B conveys H3K4me3 at bivalent and monovalent promoters in undifferentiated spermatogonia. Because these genes are expressed late in spermatogenesis or during embryogenesis, we expect that many of them are potentially programmed by KMT2B for future expression. Here, we show that one of the genes targeted by KMT2B, Tsga8, plays an essential role in spermatid morphogenesis. Loss of Tsga8 in mice leads to male infertility associated with abnormal chromosomal distribution in round spermatids, malformation of elongating spermatid heads and spermiation failure. Tsga8 depletion leads to dysregulation of thousands of genes, including the X-chromosome genes that are reactivated in spermatids, and insufficient nuclear condensation accompanied by reductions of TNP1 and PRM1, key factors for histone-to-protamine transition. Intracytoplasmic sperm injection (ICSI) of spermatids rescued the infertility phenotype, suggesting competency of the spermatid genome for fertilization. Thus, Tsga8 is a KMT2B target that is vitally necessary for spermiogenesis and fertility.
Assuntos
Fertilidade , Nucleoproteínas/metabolismo , Espermátides/metabolismo , Espermatogênese , Células-Tronco/metabolismo , Animais , Feminino , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Infertilidade Masculina/genética , Infertilidade Masculina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Nucleoproteínas/genética , Espermatogônias/metabolismoRESUMO
Respiratory failure is a life-threatening problem for pre-term and term infants, yet many causes remain unknown. Here, we present evidence that whey acidic protein (WAP) four-disulfide core domain protease inhibitor 2 (Wfdc2), a protease inhibitor previously unrecognized in respiratory disease, may be a causal factor in infant respiratory failure. Wfdc2 transcripts are detected in the embryonic lung and analysis of a Wfdc2-GFP knock-in mouse line shows that both basal and club cells, and type II alveolar epithelial cells (AECIIs), express Wfdc2 neonatally. Wfdc2-null-mutant mice display progressive atelectasis after birth with a lethal phenotype. Mutant lungs have multiple defects, including impaired cilia and the absence of mature club cells from the tracheo-bronchial airways, and malformed lamellar bodies in AECIIs. RNA sequencing shows significant activation of a pro-inflammatory pathway, but with low-quantity infiltration of mononuclear cells in the lung. These data demonstrate that Wfdc2 function is vitally important for lung aeration at birth and that gene deficiency likely causes failure of the lung mucosal barrier.
Assuntos
Insuficiência Respiratória/mortalidade , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos/fisiologia , Animais , Animais Recém-Nascidos , Diferenciação Celular , Células Cultivadas , Cílios/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos ICR , Atelectasia Pulmonar/etiologia , Surfactantes Pulmonares/metabolismoRESUMO
The structures of the title dipeptides, C9H18N2O4.0.33H2O, C12H16N2O4 and C8H16N2O4S.0.34H2O, complete a series of investigations focused on L-Xaa-L-serine peptides, where Xaa is a hydrophobic residue. All three structures are divided into hydrophilic and hydrophobic layers. The hydrophilic layers are thin for L-phenylalanyl-L-serine, rendered possible by an unusual peptide conformation, and thick for L-isoleucyl-L-serine and L-methionyl-L-serine, which include cocrystallized water molecules on the twofold axes.