Pro-neuronal activity of Myod1 due to promiscuous binding to neuronal genes

Lee, Qian Yi; Mall, Moritz; Chanda, Soham; Zhou, Bo; Sharma, Kylesh S.; Schaukowitch, Katie; Adrian-Segarra, Juan M.; Grieder, Sarah; Kareta, Michael S.; Ang, Cheen Euong; Li, Rui; Südhof, Thomas C.; Chang, Howard Y.; Wernig, Marius

doi:10.1038/s41556-020-0490-3

Cited by 41 publications

(58 citation statements)

References 67 publications

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“…4M). Cluster 1 corresponds to genes permanently repressed during PR and MT (downregulated in PRP, MTP, iPS and malignant cells when compared with PRR and MTR),including Thy1 and Bcl11b, as expected, but also Col24a1, Col4a6 and Col7a1, possibly reflecting a reorganization of the extracellular matrix(37). Clusters 2 and 3, that encompass genes transiently repressed in prone CI but reactivated respectively in malignant or iPS cells, highlighted cell adhesion molecules such as Icam1, previously identified in PR intermediates(29).…”

supporting

confidence: 54%

“…MyoD, that trigger respectively the transdifferentiation of MEF towards neuronal or muscular fates, bind the same CAGCTG E-box motif in MEF (37). By integrating the corresponding datasets, we found first that a large fraction of the Atoh8 peaks (60%) become occupied by both Ascl1 and MyoD during MEF transdifferentiation (Fig.…”

Section: Wernig and Colleagues Recently Demonstrated That The Bhlh CLmentioning

confidence: 80%

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The comprehensive roadmaps of reprogramming and transformation unveiled antagonistic roles for bHLH transcription factors in the control of cellular plasticity

Huyghe

Furlan

Schroeder

et al. 2020

Preprint

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Coordinated changes of cellular identity and plasticity are critical for pluripotent reprogramming (PR) and malignant transformation (MT). However, the molecular circuitries orchestrating these modifications, as well as their degree of analogy during reprogramming and transformation, remain unknown. To address this question, we generated “repro-transformable” mice models and dissected comparatively the early events underpinning PR - mediated by Oct4, Sox2, Klf4, c-Myc - and MT - triggered by oncogenic Ras and c-Myc. Transcriptomic analyses allowed the identification of a unique set of markers - the cell surface glycoprotein Thy1 and the transcription factor (TF) Bcl11b - that are commonly downregulated during PR and MT and delineate cellular intermediates (CI) highly amenable to generate pluripotent or malignant derivatives. Comprehensive transcriptomic, epigenomic and functional analyses of different CI, prone or refractory to PR/MT, unveiled that cellular plasticity acquisition precedes the broad extinction of cellular identity. It also demonstrated the existence of specific and shared molecular features of PR and MT while ensuring the identification of broad-range regulators of cellular plasticity. As a proof-of-concept, we revealed that the basic helix-loop-helix (bHLH) class A TF Atoh8 constrains rodent and human iPS cells generation as well as MT and direct neuron conversion. Mechanistically, this TF hampers the reactivation of the pluripotent network during PR and limits the acquisition of phenotypic plasticity during MT. Furthermore, an integrated analysis of Atoh8 genome-wide binding, alongside the other bHLH TFs c-Myc, Ascl1 and MyoD promoting reprogramming/transdifferentiation, unveiled how Atoh8 constrains cellular plasticity by occupying a specific subset of MEF enhancers and by finetuning WNT signalling activity. Collectively, by deconvoluting the early steps of the reprogramming and transformation roadmaps, this integrated study uncoupled changes of cellular plasticity and identity to shed light on novel insights into reprogramming and cancer biology.Graphical abstractOne-sentence summaryComparative roadmaps of cellular plasticity acquisition during pluripotent reprogramming and malignant transformation.

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supporting

confidence: 54%

Section: Wernig and Colleagues Recently Demonstrated That The Bhlh CLmentioning

confidence: 80%

The comprehensive roadmaps of reprogramming and transformation unveiled antagonistic roles for bHLH transcription factors in the control of cellular plasticity

Huyghe

Furlan

Schroeder

et al. 2020

Preprint

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“…We hypothesize that APOBEC2 acts as a modulator of these active promoters during the myogenic programfine-tuning it for muscle differentiation and repressing other lineage programs. MYOD1 has been shown to bind and activate lineage programs outside the muscle lineage; however, this is mitigated by co-repressors (Lee et al, 2020). Additionally, the interaction with RCOR1 ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In this gene list, we did not find an overrepresentation of GO terms relating to muscle differentiation; but rather, we found terms related to development of other lineages (Supplementary Table 1) similar to the non-muscle genes upregulated with APOBEC2 deficiency. We speculate that APOBEC2 is acting as a repressor to direct C2C12 differentiation into the muscle-lineage by repressing specious gene networks related to other lineagesfine-tuning the alleged promiscuity of muscle identity transcription factor, MYOD1 (Lee et al, 2020).…”

Section: Apobec2 Represses Expression Of Occupied Genesmentioning

confidence: 98%

APOBEC2 is a Transcriptional Repressor required for proper Myoblast Differentiation

Lorenzo

Molla

Ibarra³

et al. 2020

Preprint

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APOBEC2 is a member of the prolific activation induced cytidine deaminase/ apolipoprotein B editing complex (AID/APOBEC) family of DNA or RNA editors. This family of nucleic acid editors has diverse molecular roles ranging from antibody diversification to RNA transcript editing. However, even though APOBEC2 is an evolutionarily conserved zinc-dependent cytidine deaminase, it neither has an established molecular substrate nor function. In this work, we use the C2C12 skeletal myoblast differentiation model to confirm that APOBEC2 is upregulated during differentiation and is critical to proper differentiation. Furthermore, we show that APOBEC2 has none of the attributed molecular functions of the AID/APOBEC family, such as mRNA editing, DNA demethylation, and DNA mutation. Unexpectedly, we reveal that APOBEC2 binds chromatin at promoter regions of actively transcribed genes, and binding correlates with transcriptional repression of non-myogenesis related gene pathways. APOBEC2 occupied regions co-occur with sequence motifs for several transcription factors such as Specificity Protein/Krüppel-like Factor (SP/KLF), and we demonstrate in vitro that APOBEC2 binds directly and co-operatively to double stranded DNA containing a SP1 binding site. Finally, protein-proximity data show that APOBEC2 directly interacts with histone deacetylase (HDAC) transcriptional co-repressor complexes. Taken together, these data suggest a role for APOBEC2 as a transcriptional repressor for muscle differentiation, a novel role that is unique among AID/APOBEC family members.

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“…4B). bHLH transcription factors may be particularly suited for this, as they act as dimers with e-proteins, yet are rather promiscuous in their binding properties (29)…”

Section: Evolutionary Relationships and Diversification Of Cnidarian mentioning

confidence: 99%

Muscle cell type diversification facilitated by extensive gene duplications

Cole

Kaul

Jahnel

et al. 2020

Preprint

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The evolutionary mechanisms underlying the emergence of new cell types are still unclear. Here, we address the origin and diversification of muscle cells in the diploblastic sea anemone Nematostella vectensis. We discern two fast and two slow-contracting muscle cell populations in Nematostella differing by extensive sets of paralogous genes. The regulatory gene set of the slow cnidarian muscles and the bilaterian cardiac muscle are remarkably similar. By contrast, the two fast muscles differ substantially from each other, while driving the same set of paralogous structural protein genes. Our data suggest that extensive gene duplications and co-option of individual effector modules may have played an important role in cell type diversification during metazoan evolution.

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Pro-neuronal activity of Myod1 due to promiscuous binding to neuronal genes

Cited by 41 publications

References 67 publications

The comprehensive roadmaps of reprogramming and transformation unveiled antagonistic roles for bHLH transcription factors in the control of cellular plasticity

The comprehensive roadmaps of reprogramming and transformation unveiled antagonistic roles for bHLH transcription factors in the control of cellular plasticity

APOBEC2 is a Transcriptional Repressor required for proper Myoblast Differentiation

Muscle cell type diversification facilitated by extensive gene duplications

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