Abstract:Due to small numbers of reported patients with pathogenic variants in single genes, the phenotypic spectrum associated with genes causing neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorder is expanding. Among these genes is KLF7 (Krüppel‐like factor 7), which is located at 2q33.3 and has been implicated in several developmental processes. KLF7 has been proposed to be a candidate gene for the phenotype of autism features seen in patients with a 2q33.3q34 deletion. Her… Show more
“…5). Two of the transcription factors that were regulated in opposite directions ( NR3C1 and klf7b ) have been implicated with social behavior in other studies (the glucocorticoid receptor NR3C1 and psychosocial stress during pregnancy 39 ; klf7b and austim spectrum disorder 40 ). These patterns suggest that for some genes, different salient experiences—providing paternal care and territorial aggression—trigger opposite gene regulatory responses.Fig.…”
Motherhood is characterized by dramatic changes in brain and behavior, but less is known about fatherhood. Here we report that male sticklebacks—a small fish in which fathers provide care—experience dramatic changes in neurogenomic state as they become fathers. Some genes are unique to different stages of paternal care, some genes are shared across stages, and some genes are added to the previously acquired neurogenomic state. Comparative genomic analysis suggests that some of these neurogenomic dynamics resemble changes associated with pregnancy and reproduction in mammalian mothers. Moreover, gene regulatory analysis identifies transcription factors that are regulated in opposite directions in response to a territorial challenge versus during paternal care. Altogether these results show that some of the molecular mechanisms of parental care might be deeply conserved and might not be sex-specific, and suggest that tradeoffs between opposing social behaviors are managed at the gene regulatory level.
“…5). Two of the transcription factors that were regulated in opposite directions ( NR3C1 and klf7b ) have been implicated with social behavior in other studies (the glucocorticoid receptor NR3C1 and psychosocial stress during pregnancy 39 ; klf7b and austim spectrum disorder 40 ). These patterns suggest that for some genes, different salient experiences—providing paternal care and territorial aggression—trigger opposite gene regulatory responses.Fig.…”
Motherhood is characterized by dramatic changes in brain and behavior, but less is known about fatherhood. Here we report that male sticklebacks—a small fish in which fathers provide care—experience dramatic changes in neurogenomic state as they become fathers. Some genes are unique to different stages of paternal care, some genes are shared across stages, and some genes are added to the previously acquired neurogenomic state. Comparative genomic analysis suggests that some of these neurogenomic dynamics resemble changes associated with pregnancy and reproduction in mammalian mothers. Moreover, gene regulatory analysis identifies transcription factors that are regulated in opposite directions in response to a territorial challenge versus during paternal care. Altogether these results show that some of the molecular mechanisms of parental care might be deeply conserved and might not be sex-specific, and suggest that tradeoffs between opposing social behaviors are managed at the gene regulatory level.
“…In addition, klf7-deficient mice showed a poorer nest-building ability, which suggest a social interaction defect ( Supplementary Figure S4E ) [ 33 , 34 ]. Studies have shown that individuals with klf7 mutations are associated with intellectual disability [ 22 ]. In a novel object recognition experiment, both WT and klf7 +/− mice similarly recognized the novel object ( Supplementary Figure S4F,G ), while klf7 −/− mice showed a significantly decreased interaction time ratio (time spent interacting with the novel object/time spent interacting with the familiar object) ( Supplementary Figure S4F ) and a slightly decreased interaction frequency ratio (number of interactions with the novel object/number of interactions with the familiar object) ( Supplementary Figure S4G ).…”
Section: Resultsmentioning
confidence: 99%
“…These studies indicate a possible relationship between loss of klf7 and ASD. In addition, another study reported four unrelated individuals with de novo mutations in klf7 accompanied by ASD-related developmental delay/intellectual disability (DD/ID) and neuromuscular and psychiatric complications [ 22 ]. Owing to the transcriptional regulation activity and strong expression of klf7 in the central nervous systems [ 23 ], klf7 may be a causal gene in ASD.…”
Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disease. To date, more than 1000 genes have been shown to be associated with ASD, and only a few of these genes account for more than 1% of autism cases. Klf7 is an important transcription factor of cell proliferation and differentiation in the nervous system, but whether klf7 is involved in autism is unclear. Methods: We first performed ChIP-seq analysis of klf7 in N2A cells, then performed behavioral tests and RNA-seq in klf7+/− mice, and finally restored mice with adeno-associated virus (AAV)-mediated overexpression of klf7 in klf7+/− mice. Results: Klf7 targeted genes are enriched with ASD genes, and 631 ASD risk genes are also differentially expressed in klf7+/− mice which exhibited the core symptoms of ASD. When klf7 levels were increased in the central nervous system (CNS) in klf7+/− adult mice, deficits in social interaction, repetitive behavior and majority of dysregulated ASD genes were rescued in the adults, suggesting transcriptional regulation. Moreover, knockdown of klf7 in human brain organoids caused dysregulation of 517 ASD risk genes, 344 of which were shared with klf7+/− mice, including some high-confidence ASD genes. Conclusions: Our findings highlight a klf7 regulation of ASD genes and provide new insights into the pathogenesis of ASD and promising targets for further research on mechanisms and treatments.
“…Four unrelated individuals with de novo inactivating mutations in the Krüppel-like factor 7 (KLF7) gene exhibited autistic features along with ID (141). KLF7 is a poly-ZNF, and is essential for neurogenesis and is involved in neuronal differentiation and morphogenesis (141,142). Klf7knockout mice showed impaired axon projection in several brain regions including the cerebral cortex and hippocampus, and exhibited reduced dendritic branching in hippocampus (142).…”
Section: Involvement Of C 2 H 2 -Znfs In Asds and Down Syndromementioning
Neurodevelopmental disorders (NDDs) are multifaceted pathologic conditions manifested with intellectual disability, autistic features, psychiatric problems, motor dysfunction, and/or genetic/chromosomal abnormalities. They are associated with skewed neurogenesis and brain development, in part through dysfunction of the neural stem cells (NSCs) where abnormal transcriptional regulation on key genes play significant roles. Recent accumulated evidence highlights C 2 H 2-type zinc finger proteins (C 2 H 2-ZNFs), the largest transcription factor family in humans, as important targets for the pathologic processes associated with NDDs. In this review, we identified their significant accumulation (74 C 2 H 2-ZNFs: ∼10% of all human member proteins) in brain physiology and pathology. Specifically, we discuss their physiologic contribution to brain development, particularly focusing on their actions in NSCs. We then explain their pathologic implications in various forms of NDDs, such as morphological brain abnormalities, intellectual disabilities, and psychiatric disorders. We found an important tendency that poly-ZNFs and KRAB-ZNFs tend to be involved in the diseases that compromise gross brain structure and human-specific higher-order functions, respectively. This may be consistent with their characteristic appearance in the course of species evolution and corresponding contribution to these brain activities.
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