Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Harris, Holly K.; Nakayama, Tojo; Lai, Jenny; Zhao, Boxun; Argyrou, Nikoleta; Gubbels, Cynthia S.; Soucy, Aubrie; Genetti, Casie A.; Suslovitch, Victoria; Rodan, Lance H.; Tiller, George E.; Lesca, Gaëtan; Gripp, Karen W.; Asadollahi, Reza; Hamosh, Ada; Applegate, Carolyn D.; Turnpenny, Peter D.; Simon, Marleen; Volker‐Touw, Catharina M.L.; Gassen, Koen van; Binsbergen, Ellen van; Pfundt, Rolph; Gardeitchik, Thatjana; Vries, Bert B.A. de; Immken, La Donna; Buchanan, Catherine A.; Willing, Marcia; Toler, Tomi L.; Fassi, Emily; Baker, Laura; Vansenne, Fleur; Wang, Xiadong; Ambrus, Julian L.; Fannemel, Madeleine; Posey, Jennifer E.; Agolini, Emanuele; Novelli, Antonio; Rauch, Anita; Boonsawat, Paranchai; Fagerberg, Christina; Larsen, Martin Jakob; Kibæk, Maria; Labalme, Audrey; Poisson, Alice; Payne, Katelyn; Walsh, Laurence E.; Aldinger, Kimberly A.; Balciuniene, Jorune; Skraban, Cara; Gray, Christopher; Murrell, Jill R.; Bupp, Caleb; Pascolini, Giulia; Grammatico, Paola; Broly, Martin; Küry, Sébastien; Nizon, Mathilde; Rasool, Iqra Ghulam; Zahoor, Muhammad; Kraus, Cornelia; Reis, André; Iqbal, Muhammad Aamir; Uguen, Kévin; Audebert‐Bellanger, Séverine; Férec, Claude; Redon, Sylvia; Baker, Janice; Wu, Yunhong; Zampino, Guiseppe; Syrbe, S.; Brösse, Ines; Jamra, Rami Abou; Dobyns, William B.; Cohen, Liron; Blomhoff, Anne; Mignot, Cyril; Keren, Boris; Courtin, Thomas; Agrawal, Pankaj B.; Beggs, Alan H.; Yu, Timothy W.

doi:10.1038/s41436-021-01114-z

Cited by 40 publications

(34 citation statements)

References 39 publications

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“…Interestingly, RFX7 target gene expression correlated significantly positively with macrophage and neutrophil differentiation (Figure 6C ), indicating a potential role for RFX7 in hematopoietic differentiation that is independent of p53. Further, RFX7 target gene expression correlated positively with the differentiation of human umbilical cord blood-derived unrestricted somatic stem cells into neuronal-like cells (Figure 6C ), which is in agreement with the reported role of RFX7 in the neural development of frogs ( 19 ) and its association with neurological diseases ( 17 , 18 ). Intriguingly, the expression of RFX7 target genes correlates significantly positively also with the differentiation of human pluripotent stem cells into lung alveolar cells (Figure 6C ).…”

Section: Resultssupporting

confidence: 90%

“…RFX7 alterations have also been identified in diffuse large B cell lymphoma ( 12 ), acute myeloid leukemia ( 13 ), as well as in mouse models of lymphoma ( 12 , 14 ) and leukemia ( 15 ). In addition to hematopoietic neoplasms, RFX7 has been associated with body fat distribution ( 16 ), Alzheimer's disease ( 17 ), and autism spectrum disorder ( 18 ), suggesting that RFX7 may function in various cell types and tissues. While human RFX7 is functionally uncharacterized, first insights from animal models identified Rfx7 to play a role in anuran neural development ( 19 ) and maturation and metabolism in murine lymphoid cells ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

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Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress

Coronel

Riege

Schwab

et al. 2021

Nucleic Acids Research

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Despite its prominence, the mechanisms through which the tumor suppressor p53 regulates most genes remain unclear. Recently, the regulatory factor X 7 (RFX7) emerged as a suppressor of lymphoid neoplasms, but its regulation and target genes mediating tumor suppression remain unknown. Here, we identify a novel p53-RFX7 signaling axis. Integrative analysis of the RFX7 DNA binding landscape and the RFX7-regulated transcriptome in three distinct cell systems reveals that RFX7 directly controls multiple established tumor suppressors, including PDCD4, PIK3IP1, MXD4, and PNRC1, across cell types and is the missing link for their activation in response to p53 and stress. RFX7 target gene expression correlates with cell differentiation and better prognosis in numerous cancer types. Interestingly, we find that RFX7 sensitizes cells to Doxorubicin by promoting apoptosis. Together, our work establishes RFX7’s role as a ubiquitous regulator of cell growth and fate determination and a key node in the p53 transcriptional program.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress

Coronel

Riege

Schwab

et al. 2021

Nucleic Acids Research

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“…Likewise, for NSCs, many genes with increased expression that acquire a G4 were related to neurodevelopmental pathways such as Notch signalling e.g. DLL1 and HES1 essential for NSC maintenance 50 , SOX11 essential for NSC fate specification 51 and RFX4 , which when disrupted leads to neurodevelopmental disease 52 , 53 (Fig. 5c, d and Supplementary Figs.…”

Section: Resultsmentioning

confidence: 99%

G-quadruplex DNA structures in human stem cells and differentiation

et al. 2022

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The establishment of cell identity during embryonic development involves the activation of specific gene expression programmes and is underpinned by epigenetic factors including DNA methylation and histone post-translational modifications. G-quadruplexes are four-stranded DNA secondary structures (G4s) that have been implicated in transcriptional regulation and cancer. Here, we show that G4s are key genomic structural features linked to cellular differentiation. We find that G4s are highly abundant in human embryonic stem cells and are lost during lineage specification. G4s are prevalent in enhancers and promoters. G4s that are found in common between embryonic and downstream lineages are tightly linked to transcriptional stabilisation of genes involved in essential cellular functions as well as transitions in the histone post-translational modification landscape. Furthermore, the application of small molecules that stabilise G4s causes a delay in stem cell differentiation, keeping cells in a more pluripotent-like state. Collectively, our data highlight G4s as important epigenetic features that are coupled to stem cell pluripotency and differentiation.

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“…On the other hand, no neurodevelopmental phenotype has been described associated with RFX4 and RFX7 variants. Indeed, a very recent report by Harris and colleagues [ 8 ] describes a cohort of 38 individuals affected by similar neurodevelopmental syndromes with mostly de novo variants (30/33 variants) in RFX4 and RFX7 genes in addition to the already known RFX3 causal gene. Variants in all three genes included missense variants (thirteen), frameshift variants (eight), nonsense variants (five), splicing variants (two), and deletions (five) ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Genotype–Phenotype Correlations in Relation to Newly Emerging Monogenic Forms of Autism Spectrum Disorder and Associated Neurodevelopmental Disorders: The Importance of Phenotype Reevaluation after Pangenomic Results

Lintas

Sacco

Azzarà

et al. 2021

JCM

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ASD genetic diagnosis has dramatically improved due to NGS technologies, and many new causative genes have been discovered. Consequently, new ASD phenotypes have emerged. An extensive exome sequencing study carried out by the Autism Sequencing Consortium (ASC) was published in February 2020. The study identified 102 genes which are de novo mutated in subjects affected by autism spectrum disorder (ASD) or similar neurodevelopmental disorders (NDDs). The majority of these genes was already known to be implicated in ASD or NDDs, whereas approximately 30 genes were considered “novel” as either they were not previously associated with ASD/NDDs or very little information about them was present in the literature. The aim of this work is to review the current literature since the publication of the ASC paper to see if new data mainly concerning genotype–phenotype correlations of the novel genes have been added to the existing one. We found new important clinical and molecular data for 6 of the 30 novel genes. Though the broad and overlapping neurodevelopmental phenotypes observed in most monogenic forms of NDDs make it difficult for the clinical geneticist to address gene-specific tests, knowledge of these new data can at least help to prioritize and interpret results of pangenomic tests to some extent. Indeed, for some of the new emerging genes analyzed in the present work, specific clinical features emerged that may help the clinical geneticist to make the final diagnosis by associating the genetic test results with the phenotype. The importance of this relatively new approach known as “reverse phenotyping” will be discussed.

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Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

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Cited by 40 publications

References 39 publications

Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress

Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress

G-quadruplex DNA structures in human stem cells and differentiation

Genotype–Phenotype Correlations in Relation to Newly Emerging Monogenic Forms of Autism Spectrum Disorder and Associated Neurodevelopmental Disorders: The Importance of Phenotype Reevaluation after Pangenomic Results

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