TSPYL1 as a Critical Regulator of TGFß Signaling through Repression of TGFBR1 and TSPYL2.

Nucleosome assembly proteins (NAPs) have been identified as histone chaperons. Testis-Specific Protein, Y-Encoded-Like (TSPYL) is a newly arisen NAP family in mammals. TSPYL2 can be transcriptionally induced by DNA damage and TGFß causing proliferation arrest. TSPYL1, another TSPYL family member, has been poorly characterized and is the only TSPYL family member known to be causal of a lethal recessive disease in humans. This study shows that TSPYL1 and TSPYL2 play an opposite role in TGFß signaling. TSPYL1 partners with the transcription factor FOXA1 and histone methyltransferase EZH2, and at the same time represses TGFBR1 and epithelial-mesenchymal transition (EMT). Depletion of TSPYL1 increases TGFBR1 expression, upregulates TGFß signaling, and elevates the protein stability of TSPYL2. Intriguingly, TSPYL2 forms part of the SMAD2/3/4 signal transduction complex upon stimulation by TGFß to execute the transcriptional responses. Depletion of TSPYL2 rescues the EMT phenotype of TSPYL1 knockdown in A549 lung carcinoma cells. The data demonstrates the prime role of TSPYL2 in causing the dramatic defects in TSPYL1 deficiency. An intricate counter-balancing role of TSPYL1 and TSPYL2 in regulating TGFß signaling is also unraveled.

Reprogramming cell fates towards novel cancer immunotherapies.

Recent advances in our understanding of host immune and cancer cells interactions have made immunotherapy a prominent choice in cancer treatment. Despite such promise, cell-based immunotherapies remain inapplicable to many patients due to severe limitations in the availability and quality of immune cells isolated from donors. Reprogramming technologies that facilitate the engineering of cell types of interest, are emerging as a putative solution to such challenges. Here we focus on the recent progress being made in reprogramming technologies with respect to the immune system and their potential for clinical applications.

TSPYL1 regulates steroidogenic gene expression and male factor fertility in mice.

OBJECTIVE: To determine the importance of testis-specific, Y-encoded-like 1 (TSPYL1) in survival and male factor fertility in mice. DESIGN: Experimental prospective study. SETTING: Research laboratories in a university medical faculty. ANIMALS: We generated Tspyl1 knockout (KO) mouse lines by CRISPR/Cas9. The lines were maintained by pairing heterozygous mice to provide wild-type control and KO males for comparison. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Mendelian ratio, body and testis weight, histology, sperm motility, mating tests, pregnancy outcome, transcript levels of genes for testosterone production, and serum testosterone level. RESULT(S): A variable percentage of Tspyl1 KO mice survived beyond weaning depending on the genetic background. Growth around weaning was retarded in KO mice, but the testes-to-body weight ratio remained normal and complete spermatogenesis was revealed in testis histology. Sperm was collected from the cauda epididymis, and a significantly smaller percentage of sperm was progressively motile (22.3% ± 18.3%, n = 14 samples) compared with wild type (58.9% ± 11.5%, 11 samples). All 11 KO mice tested had defective mounting behavior. From 11 KO males paired with a total of 88 females, only one litter was born, compared with 53 litters sired by 11 age-matched wild-type males. Expression of Star, Cyp11a1, Cyp17a1, Hsd3b6, and Hsd17b3 in the KO testis was significantly reduced, while serum testosterone level was within the normal range. CONCLUSION(S): TSPYL1 is critical for survival and reproductive success in mice. TSPYL1 enhances the expression of key steroidogenic genes in the mouse testis.

Lrrc7 mutant mice model developmental emotional dysregulation that can be alleviated by mGluR5 allosteric modulation.

LRRC7 has been identified as a candidate gene for severe childhood emotional dysregulation. Direct experimental evidence for a role of LRRC7 in the disease is needed, as is a better understanding of its impact on neuronal structure and signaling, and hence potential treatment targets. Here, we generated and analyzed an Lrrc7 mutant mouse line. Consistent with a critical role of LRRC7 in emotional regulation, mutant mice had inappropriate juvenile aggressive behavior and significant anxiety-like behavior and social dysfunction in adulthood. The pivotal role of mGluR5 signaling was demonstrated by rescue of behavioral defects with augmentation of mGluR5 receptor activity by 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB). Intra-peritoneal injection of CDPPB alleviated abnormal juvenile behavior, as well as anxiety-like behavior and hypersociability at adulthood. Furthermore, mutant primary neurons had impaired neurite outgrowth which was rescued by CDPPB treatment. In conclusion, Lrrc7 mutant mice provide a valuable tool to model childhood emotional dysregulation and persistent mental health comorbidities. Moreover, our data highlight an important role of LRRC7 in mGluR5 signaling, which is a potential new treatment target for anxiety and social dysfunction.