Background Preschooling is a critical time for intervention in children with autism spectrum disorder(ASD);thus,we analyzed brain tissue component volumes(BTCVs)and clinical indicators in preschool children with ASD t...Background Preschooling is a critical time for intervention in children with autism spectrum disorder(ASD);thus,we analyzed brain tissue component volumes(BTCVs)and clinical indicators in preschool children with ASD to identify new biomarkers for early screening.Methods Eighty preschool children(3–6 years)with ASD were retrospectively included.The whole-brain myelin content(MyC),white matter(WM),gray matter(GM),cerebrospinal fluid(CSF),and non-WM/GM/MyC/CSF brain component volumes were obtained using synthetic magnetic resonance imaging(SyMRI).Clinical data,such as intelligence scores,autism diagnostic observation schedule-calibrated severity scores,age at first production of single words(AFSW),age at first production of phrases(AFP),and age at walking onset(AWO),were also collected.The correlation between the BTCV and clinical data was evaluated,and the effect of BTCVs on clinical data was assessed by a regression model.Results WM and GM volumes were positively correlated with intelligence scores(both P<0.001),but WM and GM did not affect intelligence scores(P=0.116,P=0.290).AWO was positively correlated with AFSW and AFP(both P<0.001).The multivariate linear regression analysis revealed that MyC,AFSW,AFP,and AWO were significantly different(P=0.005,P<0.001,P<0.001).Conclusions This study revealed positive correlations between WM and GM volumes and intelligence scores.Whole-brain MyC affected AFSW,AFP,and AWO in preschool children with ASD.Noninvasive quantification of BTCVs via SyMRI revealed a new visualizable and quantifiable biomarker(abnormal MyC)for early ASD screening in preschool children.展开更多
KMT2D,a H3K4me1 methyltransferase primarily regulating enhancers,is a leading cause of KABUKI syndrome.This multisystem disorder leads to craniofacial and cognitive abnormalities,possibly through neural crest and neur...KMT2D,a H3K4me1 methyltransferase primarily regulating enhancers,is a leading cause of KABUKI syndrome.This multisystem disorder leads to craniofacial and cognitive abnormalities,possibly through neural crest and neuronal lineages.However,the impacted cell-of-origin and molecular mechanism of KMT2D during the development of KABUKI disease remains unknown.Here we have optimized a brain organoid model to investigate neural crest and neuronal differentiation.To pinpoint KMT2D's enhancer target,we developed a genome-wide cis-regulatory element explorer(GREE)based on single-cell multiomic integration.Single cell RNA-seq revealed that KMT2D-knockout(KO)and patient-derived organoids exhibited neural crest deformities and GABAergic overproduction.Mechanistically,GREE identified that KMT2D targets a roof-plate-like niche cell and activates the niche cell-specific WNT3A enhancer,providing the microenvironment for neural crest and neuronal development.Interestingly,KMT2D-mutated mice displayed decreased WNT3A expression in the diencephalon roof plate,indicating impaired niche cell function.Deleting the WNT3A enhancer in the organoids presented phenotypic similarities to KMT2D-depletion,emphasizing the WNT3A enhancer as the predominant target of KMT2D.Conversely,reactivating WNT signaling in KMT2D-KO rescued the lineage defects by restoring the microenvironment.Overall,our discovery of KMT2D's primary target provides insights for reconciling complex phenotypes of KABUKI syndrome and establishes a new paradigm for dissecting the mechanisms of genetic disorders from genotype to phenotype.展开更多
基金supported by grants from the National Natural Science Foundation of China(No.81801757)Guangdong Basic and Applied Basic Research Foundation(Nos.2022A1515010369 and 2023A1515010256)Guangzhou Municipal Science and Technology Project(No.202201020421).
文摘Background Preschooling is a critical time for intervention in children with autism spectrum disorder(ASD);thus,we analyzed brain tissue component volumes(BTCVs)and clinical indicators in preschool children with ASD to identify new biomarkers for early screening.Methods Eighty preschool children(3–6 years)with ASD were retrospectively included.The whole-brain myelin content(MyC),white matter(WM),gray matter(GM),cerebrospinal fluid(CSF),and non-WM/GM/MyC/CSF brain component volumes were obtained using synthetic magnetic resonance imaging(SyMRI).Clinical data,such as intelligence scores,autism diagnostic observation schedule-calibrated severity scores,age at first production of single words(AFSW),age at first production of phrases(AFP),and age at walking onset(AWO),were also collected.The correlation between the BTCV and clinical data was evaluated,and the effect of BTCVs on clinical data was assessed by a regression model.Results WM and GM volumes were positively correlated with intelligence scores(both P<0.001),but WM and GM did not affect intelligence scores(P=0.116,P=0.290).AWO was positively correlated with AFSW and AFP(both P<0.001).The multivariate linear regression analysis revealed that MyC,AFSW,AFP,and AWO were significantly different(P=0.005,P<0.001,P<0.001).Conclusions This study revealed positive correlations between WM and GM volumes and intelligence scores.Whole-brain MyC affected AFSW,AFP,and AWO in preschool children with ASD.Noninvasive quantification of BTCVs via SyMRI revealed a new visualizable and quantifiable biomarker(abnormal MyC)for early ASD screening in preschool children.
基金supported by National Science Foundation of China(32225012)National Key R&D Program of China(2019YFA0110200)+5 种基金Health@Inno HK Program launched by Innovation Technology Commission of the Hong Kong SAR,China,Youth Innovation Promotion Association,Chinese Academy of Sciences(Jie Wang),National Science Foundation of China(32000414,32000503,and 32000501)The Science and Technology Program of Guangzhou 201804020052 and 202102021039the Pearl River Talent Recruitment Program(2021ZT09Y233)Basic Research Project of Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,(GIBHBRP23-01,GIBHBRP23-02)Frontier Science Research Program of the CAS ZDBS-LY-SM007Science and Technology Planning Project of Guangdong Province,China(2023B1212060050 and 2023B1212120009)。
文摘KMT2D,a H3K4me1 methyltransferase primarily regulating enhancers,is a leading cause of KABUKI syndrome.This multisystem disorder leads to craniofacial and cognitive abnormalities,possibly through neural crest and neuronal lineages.However,the impacted cell-of-origin and molecular mechanism of KMT2D during the development of KABUKI disease remains unknown.Here we have optimized a brain organoid model to investigate neural crest and neuronal differentiation.To pinpoint KMT2D's enhancer target,we developed a genome-wide cis-regulatory element explorer(GREE)based on single-cell multiomic integration.Single cell RNA-seq revealed that KMT2D-knockout(KO)and patient-derived organoids exhibited neural crest deformities and GABAergic overproduction.Mechanistically,GREE identified that KMT2D targets a roof-plate-like niche cell and activates the niche cell-specific WNT3A enhancer,providing the microenvironment for neural crest and neuronal development.Interestingly,KMT2D-mutated mice displayed decreased WNT3A expression in the diencephalon roof plate,indicating impaired niche cell function.Deleting the WNT3A enhancer in the organoids presented phenotypic similarities to KMT2D-depletion,emphasizing the WNT3A enhancer as the predominant target of KMT2D.Conversely,reactivating WNT signaling in KMT2D-KO rescued the lineage defects by restoring the microenvironment.Overall,our discovery of KMT2D's primary target provides insights for reconciling complex phenotypes of KABUKI syndrome and establishes a new paradigm for dissecting the mechanisms of genetic disorders from genotype to phenotype.
