H3 acetylation selectively promotes basal progenitor proliferation and neocortex expansion by activating TRNP1 expression
Posted on: 5 April 2021 , updated on: 23 June 2021
Preprint posted on 6 March 2021
Article now published in Science Advances at http://dx.doi.org/10.1126/sciadv.abc6792
Kerimoglu et al. assess epigenetic differences between mouse and human cortical basal progenitors, pointing to H3K9 acetylation as a key epigenetic mechanism controlling basal progenitor amplification in the human developing cortex.
Selected by Ana Uzquiano
Categories: cell biology, developmental biology, neuroscience
Background
The neocortex is the seat of human cognitive functions. It is a highly organized and complex region of the mammalian brain, which has undergone dramatic expansion during evolution (Cardenas and Borrell, 2019). Neocortical expansion is particularly evident in primates and hence humans, in which the neocortex constitutes the largest region of the brain (Florio and Huttner, 2014). Understanding the molecular programs underlying neocortical development and evolution is thus central to further decipher what makes us human.
Cortical development relies on different progenitor cell types which are responsible for generating the compendium of neurons populating the adult neocortex. Cortical progenitors can be subdivided in two broad categories: apical progenitors (APs) and basal progenitors (BPs). APs include apical radial glial cells (aRGs), residing in the ventricular zone (VZ) close to the ventricles. BPs derive from APs and are localized more basally in the developing cortical wall, within the subventricular zone (SVZ). BPs include intermediate progenitors (IP), and basal radial glia (bRG). Importantly, the proliferative potential of these BPs varies substantially across species. In species like the mouse, presenting a smooth (lissencephalic) cortex, BPs are mainly IPs, directly producing neurons after one round of cell division. However, in gyrencephalic species (e.g. humans), whose cortex is characterized by the presence of folds and fissures, bRGs become more abundant, and both types of BPs (i.e. IPs and bRGs) can undergo several rounds of proliferative divisions before terminally dividing to produce two postmitotic neurons (Uzquiano et al, 2018). Therefore, the different abundance of progenitor cell types and their proliferative potential are directly correlated to the final neuronal output, and ultimately to neocortical expansion.
Transcriptomics studies have provided an insight into the molecular profile characterizing different neural progenitors across different species, as well as into molecular factors that are important for BPs proliferation and neocortical expansion. Recent work capitalizing on the advent of single cell epigenome profiling is starting to shed light on the gene regulatory elements at play in specific cortical populations throughout human cortical development. However, a complete picture of the epigenetic mechanisms coordinating gene expression in different progenitor types across different species is missing. In this study, the authors compared the epigenetic profile in terms of histone (H) post-translational modifications of human and mouse BPs, identifying an increase H3K9 acetylation (H3K9ac) in human BPs. The authors reveal that H3K9ac regulates BP proliferation, and identify TRNP1 as a downstream effector of this epigenetic mechanism.
Results
First, in order to assess the epigenetic landscape of BPs, the authors FACS-sorted TBR2+ cells from mouse and human developing cortices, followed by profiling of histone post-translational modifications in these cells. In the murine and human cortices TBR2 labels IPs as well as a subset of bRGs, which are also PAX6 and HOPX positive. By this approach, the authors identified several epigenetic marks predominantly affecting H3, which were higher in human BPs compared to mouse. Amongst the epigenetic marks differing between murine and human BPs, the authors selected H3K9ac for downstream analyses since it exhibited the highest difference between both species.
In order to elucidate the functional consequences of increased H3K9ac in BPs behavior, the authors administered a histone deacetylase inhibitor, TSA, to mouse embryos. While TSA treatment for several days in utero had no effect on APs, it led to a dose-dependent increase of proliferating BPs, indicating an enhanced proliferative capacity of murine BPs upon TSA treatment due to increased H3 acetylation.
The authors then sought to identify H3K9ac target genes in BPs. They performed RNA-seq and ChIP-seq of TBR2+ and TBR2- cells of TSA and vehicle treated embryos. In order to identify functional candidates, they focused on genes exhibiting increased H3K9ac at their promoters, and after a series of filtering steps considering gene expression levels, they identified three candidates: ADRB1, TRNP1 and PCDH1.
TRNP1 has been previously shown to have a role in neural progenitor proliferation and BP genesis (Stahl et al, 2013, Martinez-Martinez et al, 2016). Here, the authors showed that gene expression and promoter H3K9ac levels of TRNP1 are higher in human BPs than in mouse BPs. To investigate directly if H3K9ac could enhance TNRP1 expression and BP proliferation, the authors directly edited H3K9ac at the TRNP1 promoter in cortical progenitors. Similar to TSA treatment, elevation of H3K9ac levels at the TRNP1 promoter led to an increase of BPs undergoing mitosis in the murine developing cortex.
Finally, the authors assessed the role of H3 acetylation in late corticogenesis by treating embryos with TSA for a longer period. Prolonged TSA treatment led to an increase in cortical radial thickness and neuron numbers. Additionally, the authors observed a fanning out of radial glial fibers as well as a mild folding of the cortex, supporting a link between BPs abundance, proliferative capacity, neocortical expansion, and ultimately gyrification. Of note, the authors obtained similar results when genetically enhancing H3K9ac levels in BPs.
In conclusion, Kerimoglu and colleagues identify epigenetic programs differing between mouse and human BPs, which mediate the proliferative potential of these progenitors and ultimately neocortical architecture.
Why I chose this paper
The high complexity of the neocortex arises during its embryonic development, which is likewise extraordinarily complex. Several features of neural progenitors, including their proliferative capacity, have been associated with neocortical expansion and gyrification. Therefore, elucidating the molecular mechanisms regulating cortical progenitor behavior across different species is key to understand human cortical development and evolution, as well as to shed light into human-specific features of brain development that may go awry in neurodevelopmental disorders.
The work by Kerimoglu et al. highlighted here contributes to our understanding of the epigenetic programs at play during murine and human corticogenesis at population-level resolution, which are still little understood. Additionally, this interspecies comparison of epigenetic marks sheds light on molecular mechanisms regulating BP behavior in the human developing cortex.
Questions for authors
By sorting TBR2+ cells, a subset of bRGs of the human developing cortex is not being sampled (TNC+, PTPRZ1+). Did you consider sorting this other subset of human bRGs to see if similar epigenetic mechanisms are at play regulating their proliferation?
Recent work has shown the presence of a bRG population in the medial cortex of the mouse which resembles more human bRGs than those present in lateral regions of the cortical wall (Vaid et al., 2018). When sorting TBR2+ cells from the mouse cerebral cortex, did you sort cells from all regions (i.e. lateral or medial)? Did you consider comparing histone post-translational modifications in BPs from the lateral vs medial cortex?
Did you consider using in vitro systems of human cortical development to directly target human BPs and decrease H3 acetylation instead of enhancing it?
Did you start studying the other two functional candidates, ADRB1 and PCDH1, whose function is unknown in the developing neocortex?
References
Cardenas, A., & Borrell, V. (2019). Molecular and cellular evolution of corticogenesis in amniotes. Cellular and Molecular Life Sciences, 77(8), 1435-1460.
Florio, M., & Huttner, W. B. (2014). Neural progenitors, neurogenesis and the evolution of the neocortex. Development, 141(11), 2182-2194.
Martinez-Martinez, M. A., De Juan Romero, C., Fernandez, V., Cardenas, A., Gotz, M., Borrell, V. (2016). A restricted period for formation of outer subventricular zone defined by Cdh1 and Trnp1 levels. Nature Communications, 7:11812.
Stahl, R., Walcher, T., De Juan Romero, C., Pilz, G. A., Cappello, S., Irmler, M., Sanz-Aquela, J.M., Beckers, J., Blum R., Borrell, V., Gotz, M. (2013). Trnp1 regulates expansion and folding of the mammalian cerebral cortex by control of radial glial fate. Cell, 153(3), 535-49.
Uzquiano, A., Gladwyn-Ng, I., Nguyen, L., Reiner, O., Gotz, M., Matsuzaki, F., Francis, F. (2018) Cortical progenitor biology, cell cycling versus neurogenesis. Journal of Neurochemistry, 146(5), 500-525.
Vaid, S., Camp, J. G., Hersemann, L., Oegema, C. E., Heninger, A.K., Winkler, S., Brandl, H., Sarov, M., Treutlein, B., Huttner, W. B., Namba, T. (2018). A novel population of Hopx-dependent basal radial glial cells in the developing mouse neocortex. Development, 145(20), dev169276.
doi: https://doi.org/10.1242/prelights.28003
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