Role of <i>ASXL1</i> mutation in impaired hematopoiesis and cellular senescence

Uni, Masahiro; Kurokawa, Mineo

doi:10.18632/oncotarget.26423

Cited by 5 publications

(5 citation statements)

References 10 publications

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“…We did not detect increased expression of gfap or sox2 relative to non-injected control (Fig 8B). Importantly, injection of Asxl1 encoding mRNA induced blood cell phenotypes consistent with a previously described function for this gene in hematopoiesis (Gjini et al, 2019; Uni and Kurokawa, 2018) (Supplemental Fig 1). The presence of blood cell phenotypes indicates functional translation of Asxl1 mRNA after injection.…”

Section: Resultssupporting

confidence: 84%

Missense and nonsense mutations of the zebrafishhcfc1agene result in contrasting mTor and radial glial phenotypes

Castro

Paz

Virrueta

et al. 2022

Preprint

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Mutations in theHCFC1transcriptional co-factor are the cause ofcblXsyndrome and X-linked intellectual disability (XLID).cblXis the more severe disorder associated with intractable epilepsy, abnormal cobalamin metabolism, facial dysmorphia, cortical gyral malformations, and intellectual disability.In vitro, Hcfc1regulates neural precursor (NPCs) proliferation and number, which has been validated in zebrafish. However, conditional deletion ofHcfc1in Nkx2.1+ NPCs increased cell death, reducedGfapexpression, and reduced numbers of GABAergic neurons. Thus, the role of HCFC1 in brain development is not completely understood. Recently, knock-in of acblX(HCFC1) andcblX-like (THAP11) were created in mice. Knock-in of thecblX-like allele was associated with increased expression of proteins required for ribosome biogenesis. However, the brain phenotypes were not comprehensively studied due to sub-viability and therefore, a mechanism underlying increased ribosome biogenesis was not described. We used a missense, a nonsense, and two conditional zebrafish alleles to further elucidate this mechanism during brain development. We observed unique subtypes ofcblXsyndrome, each with a unique signature (activation or repression) of Akt/mTor signaling. Differential regulation of mTor was associated with allele dependent radial glial cell phenotypes. Liquid chromatographmass spectrometry and chromatin immunoprecipitation revealed at least two downstream target genes of HCFC1,asxl1andywhab, whose divergent expression correlates with mTor activity in an allele specific manner. These data suggest that differential regulation of mTor across individualcblXmutations may underlie the clinical heterogeneity of patient phenotypes.Summary StatementWe uncovered a novel mechanism whereby HCFC1 regulates brain development through differential regulation of mTor activity and acts as a putative biomarker for subtypes ofcblXsyndrome.

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Section: Resultssupporting

confidence: 84%

Missense and nonsense mutations of the zebrafishhcfc1agene result in contrasting mTor and radial glial phenotypes

Castro

Paz

Virrueta

et al. 2022

Preprint

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“…However, RNA-sequencing of brain homogenates provided us a list of potential downstream effectors of hcfc1a. Of those candidates, the asxl1 gene was afforded high priority because of its known role regulating cellular proliferation [24,43,55] and for its documented function in mouse embryonic stem cells and neural differentiation [23]. Interestingly, the hcf-c1a co60/+ allele causes a 14-fold induction of asxl1 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Using literature analysis, we identified the asxl1 gene as one possible downstream effector of Hcfc1a in the developing brain. asxl1 encodes a transcriptional regulator that is essential for proper cell proliferation and whose deletion causes cellular senescence [24,43]. More importantly, mutations in ASXL1 have been associated with Boring Opitz Syndrome (605039), which has been characterized by profound intellectual disability [44].…”

Section: Overexpression Of Hcfc1 Reduces the Number Of Npcs And Decreases Neural And Glial Gene Expressionmentioning

confidence: 99%

Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain

et al. 2020

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Background Precise regulation of neural precursor cell (NPC) proliferation and differentiation is essential to ensure proper brain development and function. The HCFC1 gene encodes a transcriptional co-factor that regulates cell proliferation, and previous studies suggest that HCFC1 regulates NPC number and differentiation. However, the molecular mechanism underlying these cellular deficits has not been completely characterized. Methods Here we created a zebrafish harboring mutations in the hcfc1a gene (the hcfc1aco60/+ allele), one ortholog of HCFC1, and utilized immunohistochemistry and RNA-sequencing technology to understand the function of hcfc1a during neural development. Results The hcfc1aco60/+ allele results in an increased number of NPCs and increased expression of neuronal and glial markers. These neural developmental deficits are associated with larval hypomotility and the abnormal expression of asxl1, a polycomb transcription factor, which we identified as a downstream effector of hcfc1a. Inhibition of asxl1 activity and/or expression in larvae harboring the hcfc1aco60/+ allele completely restored the number of NPCs to normal levels. Conclusion Collectively, our data demonstrate that hcfc1a regulates NPC number, NPC proliferation, motor behavior, and brain development.

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“…However, RNA-sequencing of brain homogenates provided us a list of potential downstream candidate effectors of hcfc1a. Of those candidates, the asxl1 gene was afforded high priority because of its known role regulating cellular proliferation (24,44,56) and for its documented function in mouse embryonic stem cells and neural differentiation (23). Interestingly, the hcfc1a co60/+ allele causes a 14fold induction of asxl1 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Using literature analysis, we identified the asxl1 gene as one a possible downstream effector of Hcfc1a in the developing brain. asxl1 encodes a transcriptional regulator that is essential for proper cell proliferation and whose deletion causes cellular senescence (24,44). More importantly, mutations in ASXL1 have been associated with Boring Opitz Syndrome (605039), which has been characterized by profound intellectual disability (45).…”

Section: Overexpression Of Hcfc1 Reduces the Number Of Npcs And Decrementioning

confidence: 99%

Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain.

Castro

Reyes

Reyes-Nava

et al. 2020

Preprint

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Background: Precise regulation of neural precursor cell (NPC) proliferation and differentiation is essential to ensure proper brain development and function. The HCFC1 gene encodes a transcriptional co-factor that regulates cell proliferation, and previous studies suggest that HCFC1 regulates NPC function. However, the molecular mechanism underlying these cellular deficits has not been completely characterized. Methods: Here we created a zebrafish harboring mutations in the hcfc1a gene (the hcfc1a co60/+ allele), one ortholog of HCFC1 and utilized immunohistochemistry and RNA-sequencing technology to understand the function of hcfc1a during neural development. Results: The hcfc1a co60/+ allele results in an increased number of NPCs, neurons, and radial glial cells. These deficits are associated with the abnormal expression of asxl1 , a polycomb transcription factor, which we identified as a downstream effector of hcfc1a using high throughput RNA sequencing technology. Inhibition of asxl1 activity and/or expression in larvae harboring the hcfc1a co60/+ allele completely restored the number of NPCs to normal levels. Conclusion: Collectively, our data demonstrate a novel pathway in which hcfc1a regulates NPCs and neurogenesis.

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Role of ASXL1 mutation in impaired hematopoiesis and cellular senescence

Cited by 5 publications

References 10 publications

Missense and nonsense mutations of the zebrafishhcfc1agene result in contrasting mTor and radial glial phenotypes

Missense and nonsense mutations of the zebrafishhcfc1agene result in contrasting mTor and radial glial phenotypes

Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain

Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain.

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