BMAL1 knockout macaque monkeys display reduced sleep and psychiatric disorders

Abstract

Circadian disruption is a risk factor for metabolic, psychiatric and age-related disorders, and non-human primate models could help to develop therapeutic treatments. Here, we report the generation of BMAL1 knockout cynomolgus monkeys for circadian-related disorders by CRISPR/Cas9 editing of monkey embryos. These monkeys showed higher nocturnal locomotion and reduced sleep, which was further exacerbated by a constant light regimen. Physiological circadian disruption was reflected by the markedly dampened and arrhythmic blood hormonal levels. Furthermore, BMAL1-deficient monkeys exhibited anxiety and depression, consistent with their stably elevated blood cortisol, and defective sensory processing in auditory oddball tests found in schizophrenia patients. Ablation of BMAL1 up-regulated transcriptional programs toward inflammatory and stress responses, with transcription networks associated with human sleep deprivation, major depressive disorders, and aging. Thus, BMAL1 knockout monkeys are potentially useful for studying the physiological consequences of circadian disturbance, and for developing therapies for circadian and psychiatric disorders.

Chicken cecal DNA methylome alteration in the response to Salmonella enterica serovar Enteritidis inoculation

“…Rhythmic process plays a dominant role in determining overall health and physiological homeostasis and could facilitate the organism to survive well in different circumstances. There was a direct molecular link existed between circadian dysregulation and diseases [54]. It has been revealed that circadian rhythm related genes play critical roles in the host response to C. jejuni colonization in chicken [50].…”

Recent advances in CRISPR research

“…But for large animals, the most efficient way to get gene-edited animal is by directly injection of CRISPR system into zygote and embryo transfer performed later. As the improving of efficiency and specificity of CRISPR system, it is increasingly being used in large animals like monkeys (Zhang et al, 2018 ; Qiu et al, 2019 ; Zhou et al, 2019b ). But one of the drawbacks with CRISPR system is that the same gRNA usually causes various genome types between cells and individuals, so it will be hard to obtained “identical” animal models for one disease mutation.…”

“…Using the edited cells with the same genome typing as donor cells, the clone animals will have the same genetic background. Through this way, Huntington’s disease pigs and a BMAL1-ablation macaque have been established in recent researches (Yan et al, 2018 ; Qiu et al, 2019 ). With the improving of SCNT, such an approach will be the most efficient way to generating large animal models of human diseases, including non-human primate models.…”

Hedgehog signaling keeps liver clock in check

“…In a ground-breaking report, published in 2019, Chinese researchers reported the generation of a monkey harboring deletion of the BMAL1 circadian gene, using CRISPR/Cas9 editing of monkey embryos. 1 Not surprisingly, these monkeys exhibit insomnia and psychiatric disorders, producing a horrifying ethical minefield and widespread protests. In fact, it is already well known that circadian disruption is a risk factor for metabolic, psychiatric and age-related disorders, in an intertwined fashion.…”