Role of PIWI-like 4 in modulating neuronal differentiation from human embryonal carcinoma cells

Subhramanyam, Charannya Sozheesvari; Cao, Qian; Wang, Cheng; Heng, Zealyn Shi Lin; Zhou, Zhihong; Hu, Qidong

doi:10.1080/15476286.2020.1757896

Cited by 17 publications

(15 citation statements)

References 63 publications

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“…Kdm6a plays a key role in cell fate determination and cellular identity during development by controlling pluripotency and lineagespecific sets of genes [21,22]. During brain development, Kdm6a is involved in neurogenesis promotion, determining the neural stem cell status and modulating the subsequent differentiation of these pluripotent cells into neurons and glia [23][24][25][26]. Regarding neuronal differentiation, it has been shown that Kdm6a deletion prevents the proper development and maturation of neurons, leading to a repression of genes required for neuritogenesis and synaptogenesis (such as CREB5, CAMK2A, CKB, ASIC1, and ASCL1, among many others), defects and immaturity in dendritic arborization and synapse formation, failures in electrophysiological activity, increased expression of anxious behaviors, and deficits in spatial learning and memory [27,28].…”

Section: Introductionmentioning

confidence: 99%

X-linked histone H3K27 demethylase Kdm6a regulates sexually dimorphic differentiation of hypothalamic neurons

Zapata

Cisternas

Sosa

et al. 2021

Cell. Mol. Life Sci.

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Several X-linked genes are involved in neuronal differentiation and may contribute to the generation of sex dimorphisms in the brain. Previous results showed that XX hypothalamic neurons grow faster, have longer axons, and exhibit higher expression of the neuritogenic gene neurogenin 3 (Ngn3) than XY before perinatal masculinization. Here we evaluated the participation of candidate X-linked genes in the development of these sex differences, focusing mainly on Kdm6a, a gene encoding for an H3K27 demethylase with functions controlling gene expression genome-wide. We established hypothalamic neuronal cultures from wild-type or transgenic Four Core Genotypes mice, a model that allows evaluating the effect of sex chromosomes independently of gonadal type. X-linked genes Kdm6a, Eif2s3x and Ddx3x showed higher expression in XX compared to XY neurons, regardless of gonadal sex. Moreover, Kdm6a expression pattern with higher mRNA levels in XX than XY did not change with age at E14, P0, and P60 in hypothalamus or under 17β-estradiol treatment in culture. Kdm6a pharmacological blockade by GSK-J4 reduced axonal length only in female neurons and decreased the expression of neuritogenic genes Neurod1, Neurod2 and Cdk5r1 in both sexes equally, while a sex-specific effect was observed in Ngn3. Finally, Kdm6a downregulation using siRNA reduced axonal length and Ngn3 expression only in female neurons, abolishing the sex differences observed in control conditions. Altogether, these results point to Kdm6a as a key mediator of the higher axogenesis and Ngn3 expression observed in XX neurons before the critical period of brain masculinization.

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Section: Introductionmentioning

confidence: 99%

X-linked histone H3K27 demethylase Kdm6a regulates sexually dimorphic differentiation of hypothalamic neurons

Zapata

Cisternas

Sosa

et al. 2021

Cell. Mol. Life Sci.

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“…PIWIL3 has not been reported previously in brain, as it has in ovary, testis, and blood [ 15 ]. The role of PIWIL4 in brain is poorly understood, despite recent reports indicating that PIWIL2 and PIWIL4 are associated with autism [ 27 ], and that PIWIL4 helps modulate neuronal differentiation from human embryonal carcinoma cells [ 28 ]. Disturbance of these tissue specificities of PIWI proteins, or dysfunction of PIWIL4 may also contribute to the disease signature of ALS.…”

Section: Discussionmentioning

confidence: 99%

piRNA/PIWI Protein Complex as a Potential Biomarker in Sporadic Amyotrophic Lateral Sclerosis

et al. 2022

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The pathological hallmark of the majority of amyotrophic lateral sclerosis (ALS) cases is the mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43), an RNA-binding protein. Several studies have attributed disease processes of ALS to abnormal RNA metabolism. However, dysregulated biogenesis of RNA, especially non-coding RNA (ncRNA), is poorly understood. To resolve it, RNA-Seq, biochemical, and immunohistochemical analyses were performed on the pyramidal tract of the medulla oblongata of sporadic ALS (sALS) and control postmortem brain samples. Here, we report perturbation of ncRNA biogenesis in PIWI-interacting RNA (piRNA) in several sALS brain samples associated with TDP-43 pathology. In addition, we confirmed the dysregulation of two PIWI homologs, PIWI-like-mediated gene silencing 1 (PIWIL1) and PIWIL4, which bind to piRNAs to regulate their expression. PIWIL1 was mislocalized and co-localized with TDP-43 in motor neurons of sporadic ALS lumbar cords. Our results imply that dysregulation of piRNA, PIWIL1, and PIWIL4 is linked to pathogenesis of ALS. Based on these results, piRNAs and PIWI proteins are potential diagnostic biomarkers and therapeutic targets of ALS.

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“…Consistent with this, we have previously reported higher levels of Kdm6a expression in XX than in XY hypothalamic neurons and a female-specific requirement for the demethylase in mediating increased axogenesis before brain exposure to gonadal hormones ( Cabrera Zapata et al, 2021 ). While Kdm6a is dispensable for the maintenance of embryonic stem cells, it plays a critical role in the determination of neural stem cells and the subsequent differentiation of these pluripotent cells into neurons and glia ( Wang et al, 2012 ; Lei and Jiao, 2018 ; Yang et al, 2019 ; Shan et al, 2020 ; Subhramanyam et al, 2020 ), with deletion of Kdm6a leading to impaired dendritic arborization, synaptic formation, electrophysiological activity and cognition ( Tang et al, 2017 ; Tang et al, 2020 ), and loss-of-function mutations in KDM6A causing cognitive deficits in humans ( Miyake et al, 2013 ; Van Laarhoven et al, 2015 ; Bogershausen et al, 2016 ; Faundes et al, 2021 ). Herein, we investigated the role of Kdm6a in the specification of neuronal subtypes in the developing hypothalamus and its differential requirements in males and females, focusing mainly on Pomc+ and Npy+ neuronal populations as essential elements in the central control of food intake and energy homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic modifier Kdm6a/Utx controls the specification of hypothalamic neuronal subtypes in a sex-dependent manner

Zapata

Cambiasso

Arévalo

2022

Front. Cell Dev. Biol.

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Kdm6a is an X-chromosome-linked H3K27me2/3 demethylase that promotes chromatin accessibility and gene transcription and is critical for tissue/cell-specific differentiation. Previous results showed higher Kdm6a levels in XX than in XY hypothalamic neurons and a female-specific requirement for Kdm6a in mediating increased axogenesis before brain masculinization. Here, we explored the sex-specific role of Kdm6a in the specification of neuronal subtypes in the developing hypothalamus. Hypothalamic neuronal cultures were established from sex-segregated E14 mouse embryos and transfected with siRNAs to knockdown Kdm6a expression (Kdm6a-KD). We evaluated the effect of Kdm6a-KD on Ngn3 expression, a bHLH transcription factor regulating neuronal sub-specification in hypothalamus. Kdm6a-KD decreased Ngn3 expression in females but not in males, abolishing basal sex differences. Then, we analyzed Kdm6a-KD effect on Ascl1, Pomc, Npy, Sf1, Gad1, and Th expression by RT-qPCR. While Kdm6a-KD downregulated Ascl1 in both sexes equally, we found sex-specific effects for Pomc, Npy, and Th. Pomc and Th expressed higher in female than in male neurons, and Kdm6a-KD reduced their levels only in females, while Npy expressed higher in male than in female neurons, and Kdm6a-KD upregulated its expression only in females. Identical results were found by immunofluorescence for Pomc and Npy neuropeptides. Finally, using ChIP-qPCR, we found higher H3K27me3 levels at Ngn3, Pomc, and Npy promoters in male neurons, in line with Kdm6a higher expression and demethylase activity in females. At all three promoters, Kdm6a-KD induced an enrichment of H3K27me3 only in females. These results indicate that Kdm6a plays a sex-specific role in controlling the expression of transcription factors and neuropeptides critical for the differentiation of hypothalamic neuronal populations regulating food intake and energy homeostasis.

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Role of PIWI-like 4 in modulating neuronal differentiation from human embryonal carcinoma cells

Cited by 17 publications

References 63 publications

X-linked histone H3K27 demethylase Kdm6a regulates sexually dimorphic differentiation of hypothalamic neurons

X-linked histone H3K27 demethylase Kdm6a regulates sexually dimorphic differentiation of hypothalamic neurons

piRNA/PIWI Protein Complex as a Potential Biomarker in Sporadic Amyotrophic Lateral Sclerosis

Epigenetic modifier Kdm6a/Utx controls the specification of hypothalamic neuronal subtypes in a sex-dependent manner

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