Transcriptional repression by FEZF2 restricts alternative identities of cortical projection neurons

Tsyporin, Jeremiah; Tastad, David; Ma, Xiaokuang; Nehme, Antoine; Finn, Thomas S.; Huebner, Liora; Liu, Shuai; Gallardo, Daisy; Makhamreh, Amr; Roberts, Jacqueline M.; Katzman, Solomon; Šestan, Nenad; McConnell, Susan K.; Yang, Zhengang; Qiu, Shenfeng; Chen, Bin

doi:10.1016/j.celrep.2021.109269

Cited by 37 publications

(63 citation statements)

References 55 publications

(103 reference statements)

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“…(5) similarly, TF repression of alternative neuron-type effector genes during terminal differentiation has been widely reported (Baum et al, 1999;Borromeo et al, 2014;Gordon & Hobert, 2015;Kerk et al, 2017;Remesal et al, 2020;Smith, O'Brien, et al, 2013;Tsyporin et al, 2021;Zheng et al, 2018) and ( 6), finally, active repression of alternative fates in mature neurons has also been observed. Adult removal of Nrl bZIP TF, a TF required for rod photoreceptor terminal differentiation, produces loss of rod effector gene expression, concomitant de-repression of cone effector genes, including two cone opsins, and acquisition of some morphological and electrical properties of cone cells (Montana et al, 2013).…”

Section: The Prevalence Of Repression In the Establishment Of Neurona...mentioning

confidence: 84%

Transcriptional regulation of neuronal identity

Sousa

Flames

2022

Eur J of Neuroscience

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Neuronal diversity is an intrinsic feature of the nervous system. Transcription factors (TFs) are key regulators in the establishment of different neuronal identities; how are the actions of different TFs coordinated to orchestrate this diversity? Are there common features shared among the different neuron types of an organism or even among different animal groups? In this review, we provide a brief overview on common traits emerging on the transcriptional regulation of neuron type diversification with a special focus on the comparison between mouse and Caenorhabditis elegans model systems. In the first part, we describe general concepts on neuronal identity and transcriptional regulation of gene expression. In the second part of the review, TFs are classified in different categories according to their key roles at specific steps along the protracted process of neuronal specification and differentiation. The same TF categories can be identified both in mammals and nematodes. Importantly, TFs are very pleiotropic: Depending on the neuron type or the time in development, the same TF can fulfil functions belonging to different categories. Finally, we describe the key role of transcriptional repression at all steps We at EJN are pleased to introduce Nuria Flames in our "Trailblazers in Neuroscience" series, see Editorial https://onlinelibrary.wiley.com/doi/10. 1111/ejn.15201. Nuria Flames' reflections on undertaking a career as a neuroscientist can be found at the end of the review. You can read other Trailblazers Reviews in the series here.

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Section: The Prevalence Of Repression In the Establishment Of Neurona...mentioning

confidence: 84%

Transcriptional regulation of neuronal identity

Sousa

Flames

2022

Eur J of Neuroscience

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“…Superior to standard DEX analyses that are based solely on expression levels, PGA identifies genes not only by up- or downregulation between conditions, but also with nonrandom patterns along pseudotime, which we refer to as “association.” We identified ten genes that were specifically associated with trisomic cells in ExN4 including ephrin type-A receptor 3 ( EPHA3) and myocyte enhancer factor 2C ( MEF2C ), which have been shown to function in motility and migration during neural development ( Figure 4G, Table 1 and Supplemental Figure 7) . Among the genes unassociated with trisomic cells in ExN4 were several neuronal transcription factors such as BCL11B and FEZF2 , as well as protocadherins, PCDH17 and PCDH19 , all of which play key roles in cortical development ( Figure 4G, Table 1 and Supplemental Figure 7 ) (Chang et al, 2018; Du et al, 2021; Hoshina et al, 2021; Sadegh et al, 2021; Tsyporin et al, 2021). To validate the findings from scRNA-seq, we examined the protein expression of deep and superficial cortical layer markers, BCL11B (CTIP2) and SATB2, respectively in CS.…”

Section: Resultsmentioning

confidence: 99%

Asynchronous excitatory neuron development in an isogenic cortical spheroid model of Down syndrome

Klein

Rampam

et al. 2022

Preprint

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The intellectual disability (ID) in Down syndrome (DS) is thought to result from a variety of developmental deficits such as alterations in neural progenitor division, neurogenesis, gliogenesis, cortical architecture, and reduced cortical volume. However, the molecular processes underlying these neurodevelopmental changes are still elusive, preventing an understanding of the mechanistic basis of ID in DS. In this study, we used a pair of isogenic (trisomic and euploid) induced pluripotent stem cell (iPSC) lines to generate cortical spheroids (CS) that model the impact of trisomy 21 on brain development. CS contain neurons, astrocytes, and oligodendrocytes and they are widely used to approximate early neurodevelopment. Using single cell RNA sequencing (scRNA-seq), we uncovered cell type-specific transcriptomic changes in the trisomic CS. In particular, we found that excitatory neuron populations were most affected and that a specific population of cells with a transcriptomic profile resembling layer IV cortical neurons displayed the most profound divergence in developmental trajectory between trisomic and euploid genotypes. We also identified candidate genes potentially driving the developmental asynchrony between trisomic and euploid excitatory neurons. Direct comparison between the current isogenic CS scRNA-seq data and previously published datasets revealed several recurring differentially expressed genes between DS and control samples. Altogether, our study highlights the power and importance of cell type-specific analyses within a defined genetic background, coupled with broader examination of mixed samples, to comprehensively evaluate cellular phenotypes in the context of DS.

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“…The postmitotic accumulation of H3.3 coincided with an important period of molecular identity acquisition for new neurons (50-61). To determine whether H3f3a / H3f3b co-deletion affected the developmental establishment of the transcriptional landscape, we intersected genes that were significantly downregulated (579), upregulated (369), or unchanged (3128, FDR > 0.9, -0.1 < log 2 FC < 0.1, log 2 CPM > 1) in dKO-N with ENCODE wildtype forebrain expression data from E10.5 to P0 (62).…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have identified a number of key transcription factors that function postmitotically to specify the identities of new cortical neurons (50-61). We find that postmitotic co-deletion of H3f3a and H3f3b (dKO-N) abrogates de novo H3.3 accumulation during this critical period, and alters the deposition and removal of H3 PTMs H3K4me3 and H3K27me3, thus disrupting the establishment of the chromatin landscape.…”

Section: Discussionmentioning

confidence: 99%

“…The acquisition of neuronal identity occurs under precise regulation, starting with cell fate specification at the level of NPCs (41, 73). Neuronal identities are however not entirely established within NPCs; a number of transcription factors function postmitotically to refine neuronal identities (50-61). Following postmitotic H3f3a / H3f3b deletion in dKO-N, we find a broad spectrum of disruptions to transcription factors that regulate neuronal fates, ranging from near complete losses, to shifts in laminar domains, to increases in aberrant co-expression.…”

Section: Discussionmentioning

confidence: 99%

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Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity

Funk

Qalieh

Doyle

et al. 2021

Preprint

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Histone variants, which can be expressed outside of S-phase and deposited DNA synthesis-independently, provide replacement histones in terminally post-mitotic cells, including neurons. Histone variants can also serve active roles in gene regulation by modulating chromatin states or enabling nucleosome turnover at regulatory regions. Here, we find that newborn cortical excitatory neurons substantially accumulate the histone H3 variant H3.3 immediately post-mitosis. Co-deletion of H3.3-encoding genes H3f3a and H3f3b from new neurons abrogates this accumulation, and causes widespread disruptions in the developmental establishment of the neuronal transcriptome. These broad transcriptomic changes coincide with neuronal maturation phenotypes in acquisition of distinct neuronal identities and formation of axon tracts. Stage-dependent deletion of H3f3a and H3f3b from (1) cycling neural progenitor cells, (2) neurons immediately after terminal mitosis, or (3) several days later, reveals the first post-mitotic days as a critical window for de novo H3.3. After H3.3 accumulation within this developmental window, co-deletion of H3f3a and H3f3b from neurons causes progressive H3.3 depletion over several months without widespread transcriptional disruptions. Our study thus uncovers a key role for H3.3 in establishing neuronal transcriptome, identity, and connectivity immediately post-mitosis that is distinct from its role in maintaining total histone H3 levels over the neuronal lifespan.SignificanceDNA is tightly packaged around histones into chromatin, which compacts the genome, but also restricts access to DNA. All transactions on DNA, notably gene transcription, require chromatin reorganization that is precisely regulated, including via the use of variant forms of histones. Here, we find that during a critical developmental window for establishing post-mitotic neuronal identity, newly generated cortical excitatory neurons substantially accumulate the histone H3 variant H3.3 immediately after terminal mitosis. Conditional deletion of H3.3-encoding genes from new neurons abrogates this accumulation, and disrupts neuronal gene expression, subtype identity, and axon projections. Thus, H3.3 plays important roles in establishing neuronal transcriptome, identity, and connectivity during post-mitotic development. These functions are distinct from long-term maintenance of histone levels in mature neurons.

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Transcriptional repression by FEZF2 restricts alternative identities of cortical projection neurons

Cited by 37 publications

References 55 publications

Transcriptional regulation of neuronal identity

Transcriptional regulation of neuronal identity

Asynchronous excitatory neuron development in an isogenic cortical spheroid model of Down syndrome

Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity

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