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W4385234394 abstract "Full text Figures and data Side by side Abstract Editor's evaluation Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract The dorsal telencephalon (i.e. the pallium) exhibits high anatomical diversity across vertebrate classes. The non-mammalian dorsal pallium accommodates various compartmentalized structures among species. The developmental, functional, and evolutional diversity of the dorsal pallium remain unillustrated. Here, we analyzed the structure and epigenetic landscapes of cell lineages in the telencephalon of medaka fish (Oryzias latipes) that possesses a clearly delineated dorsal pallium (Dd2). We found that pallial anatomical regions, including Dd2, are formed by mutually exclusive clonal units, and that each pallium compartment exhibits a distinct epigenetic landscape. In particular, Dd2 possesses a unique open chromatin pattern that preferentially targets synaptic genes. Indeed, Dd2 shows a high density of synapses. Finally, we identified several transcription factors as candidate regulators. Taken together, we suggest that cell lineages are the basic components for the functional regionalization in the pallial anatomical compartments and that their changes have been the driving force for evolutionary diversity. Editor's evaluation This important article highlights the clonal organization of the dorsal telencephalon, a major region of the vertebrate brain. The authors’ analyses reveal a distinct gene expression and provide a high-quality chromatin accessibility map of the adult teleost fish medaka. In addition, synaptic genes have a distinct chromatin landscape and expression pattern from one of the regions of the dorsal pallium, aiming to describe an evolutionary origin for these neurons. https://doi.org/10.7554/eLife.85093.sa0 Decision letter Reviews on Sciety eLife's review process Introduction The telencephalon is an essential brain part for an animal’s cognitive functions and is highly diverse in structure among vertebrates. The dorsal telencephalon, or the pallium, is divided into several distinct regions in mammals; for example, the cerebral neocortex in the mammalian dorsal pallium (MDP), the hippocampus in the mammalian medial pallium (MMP), and the basolateral amygdala in the mammalian lateral pallium (MLP) (Briscoe and Ragsdale, 2019; Yamamoto et al., 2007; Northcutt, 2011; Yamamoto et al., 2017). The MDP is characterized by a six-layered structure and by stereotypical projections from all sensory modalities. The non-mammalian dorsal pallium generally lacks a multilayered structure, with the exception of non-avian reptiles (Aboitiz et al., 2002; Aboitiz et al., 2003), but rather exhibits a compartmentalized architecture that is highly diverse across species. Little is known about how the anatomical diversity in the dorsal pallium has emerged during evolution. Nonetheless, the neocortex in mammals, as well as the dorsal pallium in non-mammalian clades, receives structured input from all sensory modalities, and these structures therefore are hypothesized to fulfill similar function. In teleost, the number of compartments in the dorsal pallium is also quite diverse among species. Somatosensory input into the dorsal pallium in marbled rockfish (Yamamoto et al., 2007; Ito et al., 1986) and visual projections from the optic tectum in the yellowfin goby (Hagio et al., 2021; Hagio et al., 2018; Bloch et al., 2020) are just a few specific examples of such sensory projections. However, because of the lack of genetic tools in these species, the molecular characterization of the dorsal pallium in teleosts is still largely underexplored. In zebrafish (Danio rerio), the most popular fish model organism, a clear dorsal pallium could not be delineated (Porter and Mueller, 2020; Mueller et al., 2011), which has made a detailed characterization difficult in this species. To study how the specific architecture of the dorsal pallium in teleosts emerges and is maintained throughout life, we combined two orthogonal approaches. First, cell lineage analysis was used to visualize cellular subpopulations derived from the same neural stem cells at an early developmental stage. Since post-hatch neurogenesis occurs throughout life in all teleosts, such cell lineage analysis of neural progenitors allows us to collectively label individual neural progenitors populations that may serve similar functions (Raj et al., 2018; Furlan et al., 2017; Dirian et al., 2014). Second, for characterizing gene expression within these clonal units, we focused on epigenetic regulation of transcription, where ATAC-sequencing (Letelier, 2018; Yin et al., 2020) allows for the identification of specifically regulated genes within each population, whose expression levels are further quantified by subsequent RNA-sequencing. Here, we selected medaka fish (Oryzias latipes) as a model organism for three reasons. First, medaka possesses a dorsal pallium (Dd2) that is demarcated by a cellular boundary, which makes it anatomically distinct (Anken and Bourrat, 1998) and facilitates the isolation of this particular region. Second, transgenic medaka lines are available to visualize cell lineages in the brain (Okuyama et al., 2013). Third, the genome size of medaka is smaller than that of zebrafish (Kasahara et al., 2007), the genome sequence is of high quality (Ichikawa et al., 2017), and it is readily available for epigenetic analysis (Nakamura et al., 2021; Cheung et al., 2017). We first investigated the clonal architecture of the entire telencephalon in medaka and found that all anatomical regions within the pallium, including Dd2, are formed by mutually exclusive clonal units. We next investigated that clonal units in Dd2 in particular possess a unique open chromatin landscape, where synaptic genes were actively regulated. Subsequently, we examined the transcriptional regulatory mechanism in Dd2 to identify some candidate transcription factors (TFs) that contribute to the unique epigenetic landscape in the dorsal pallium. Our data suggest that clonal units in the pallium show modular properties, and in particular, the dorsal pallium is constructed with distinct synaptic architecture according to different rules from those of other pallial regions. Results Anatomical regions in the adult medaka pallium consist of cell bodies of cell lineages Other than in mammals, the teleost brain grows continuously throughout life via post-hatch neurogenesis (Kuroyanagi et al., 2010; Figure 1A, left), such that the anatomical classification framework needs to be adapted to this expansion. For example, the nomenclature of the adult medaka telencephalon has been complicated by the difficulties in identifying the small brain structures that emerge in adult brain sections throughout development (Anken and Bourrat, 1998; Ishikawa et al., 1999). Here, we first redefined the anatomical regions in the medaka telencephalon based on the three-dimensional distribution of cell nuclei by DAPI staining and tissue clearing (Figure 1A, right, Figure 1—figure supplement 1, Video 1). To acquire optical sections of the whole adult telencephalon, we applied a tissue clearing solution, ScaleA2 (Hama et al., 2011,) followed by light-sheet microscopic imaging. We also defined the anatomical regions by immunostaining of cell-type-specific neural markers, such as CaMK2α, parvalbumin, and GAD65/67 (Table 1, Figure 1—figure supplement 2). Here, we redefined the medial part of the pallial region (Dm) into several subcompartments (Dm2a, Dm2b, Dm3a, and Dm3b) by clear DAPI-positive boundaries. These subcompartments are absent in previous brain atlases. Also, we found clear anatomical boundaries in the dorsal pallium where different marker genes are expressed along the anterior–posterior axis (Dd2a, 2p) (Figure 1A, right, Figure 1—figure supplement 2A; a detailed description of nomenclature is provided in Table 2). Figure 1 with 4 supplements see all Download asset Open asset Clonal architecture in the adult medaka telencephalon. (A) A larval medaka fish (1 week day post fertilization) and a dissected adult brain (top left). Pink triangles indicate the position of the telencephalon in the larval and adult brain. The white two-way arrows indicate the length of the whole larval brain. Scale bar: 1 mm. Schematic drawing of the lateral view of the adult telencephalon (pink, bottom left). Horizontal and vertical lines indicate the position of optical sections in the brain atlas on the right panel. Redefined anatomical regions of adult medaka telencephalon are shown (right). Optical horizontal sections (top right) and transverse sections (bottom right). Orange triangles indicate the position of the dorsal pallial regions we focus on (dark orange: Dd2a; light orange: Dd2p). For each section, the left picture shows DAPI signals and the right shows the brain atlas. (B) Experimental procedure to label cell lineages. Cre-loxp recombination was induced by a short heat shock at the neurula stage of transgenic embryos (Tg (HuC:loxp-DsRed-loxp-GFP) × Tg(HSP:Cre)). Dissected brains were stained with DAPI, cleared in Scale solution, and light-sheet microscopy images were taken. Fluorescent signals were registered to a reference telencephalon. Optical horizontal and transverse sections are shown (i, ii). A: anterior direction; D: dorsal direction; L: lateral direction. (C) Examples of anatomical regions consist of clonally related cells. Multiple cell lineages mix and constitute the subpallial regions, for example, the dorsal medial part of the subpallium (Vd) (an example image from a single fish’s optical section is shown [i]), while the pallium consists of cell lineages in an exclusive mosaic pattern. The clonally related cells in the dorsal part of the lateral pallium (Dld) are shown as an example (ii). A: anterior; P: posterior direction. Scale bar: 100um. (D) Examples of the structure of cell lineages identified in the telencephalon. Dorsal views are shown. Colors of cell lineages indicate the position of cell somas in the anatomical region in (A). Dc: the dorso-central telencephalon; Dcpm: the posterior medial nucleus of the dorso-central telencephalon; Dm: the medial part of the dorsal pallium; Dl: the dorsal lateral pallium; Dla: the anterior part of the dorso-lateral telencephalon; Dld: the dorsal part of the middle and posterior part of the dorso-lateral telencephalon; Dlv: the ventral part of the middle and posterior part of the dorso-lateral telencephalon; Dlp: the posterior regions of the dorso-lateral telencephalon; Dd: the dorso-dorsal telencephalon; Dp: the posterior part of dorsal telencephalon; Vd: the dorsal medial part of the subpallium; Vs: the supracommissural part of ventral telencephalon; Vv: the ventral part of the subpallium; ECL: the external layer of the olfactory bulb; ICL: the internal layer of the olfactory bulb. Table 1 Summary of marker gene expression in the telencephalic regions in medaka. Several marker gene expressions were assessed with immunostainings (Figure 1—figure supplement 2). CaMK2ParvalbuminGAD65/67GAD67Dla+n.a.n.a.n.a.Dld＋/–++＋＋Dlp＋/––-n.a.Dlv+++＋＋Dd1＋＋＋-+Dd2a＋＋＋＋＋+Dd2p＋＋(ventral)＋＋＋(dorsal)+Dm1–ー+n.a.Dm2a＋–++Dm2b＋＋–++Dm3a＋＋ー++Dm3b＋＋ー++Dm4＋＋＋＋-n.a.Dp＋＋＋-n.a.Dc＋--n.a.Dcpm–-n.a.n.a.GL＋n.a.＋＋+ICL–＋＋n.a.n.a.Vv–＋＋--Vd–＋＋--Vp＋＋+--Vs–+--Vl–＋＋-- - signals not detected; +: signals detected; ++: signals strongly detected; n.a.: not analyzed. Table 2 Nomenclature of the adult telencephalon. For the medaka brain research, two brain atlases of adult medaka have been used (Anken and Bourrat, 1998; Ishikawa et al., 1999). Because performing three-dimensional reconstruction from brain slices is difficult, some inconsistencies in nomenclature were observed among references. To overcome this difficulty, we performed a three-dimensional imaging of the nuclei-stained adult medaka telencephalon, which allowed us to analyze the anatomical boundaries in more accuracy. The number in the name of anatomical regions (such as Dm1, Dm2, Dm3) was defined by the order of the emergence in the anterior to posterior axis. Here, the table shows the nomenclature of the anatomical regions of the adult telencephalon and the description of cellular organization in the anatomical regions, which we used to define the names. Abbreviation of anatomical regionName of subregionName of anatomical regionCellular distributionDcThe dorso-central telencephalonIn most teleostean species, cells in Dc have larger size of cell body (Cichlid fish Burmeister et al., 2009, sea bass Cerdá-Reverter et al., 2001) and are sparsely distributed. According to the medaka brain atlas of Ishikawa et al., 1999, Dc is defined in the center of the pallium as well. However, in the other brain atlas of medaka fish (Anken and Bourrat, 1998), multiple subregions are separately defined as Dcs. In our atlas, we defined the center region of the pallium that has less dense cell populations as Dc.DcpmThe posterior medial nucleus of the dorso-central telencephalonThe aggregates of cells in the posterior medial center of dorsal pallium (Dcpm) were found.DmThe medial part of the dorsal palliumSmall cell-body neurons with high density were observed. In the horizontal optic sections, we found several linearly aligned cells on the dorsal surface of the telencephalic hemispheres which correspond to the boundaries of Dm subregions.Dm1Densely packed with small cells.Dm2Dm2 is packed with cells more densely than Dm1.Dm3Dm4DlThe dorsal lateral palliumIn the previous medaka brain atlas, the anterior region of dorsal lateral pallium is simply named as Dl (Anken and Bourrat, 1998). But here we named this anterior part of dorso-lateral telencephalon the Dla because the nuclear density is less than Dld, Dlv, and Dlp. We also divided Dl into the dorsal and ventral part since the nuclear density is different between the dorsal and ventral parts.DlaThe anterior part of the dorso-lateral telencephalonIn the horizontal sections, we found that the density of nucleuses are more sparse in Dla than Dld and Dlv.DldThe dorsal part of the middle and posterior part of the dorso-lateral telencephalonThe dorsal part of the middle and posterior part of the dorso-lateral telencephalon (Dld) (Anken and Bourrat, 1998) is next to Dla and the cell density is more than that of Dla.DlvThe ventral part of the middle and posterior part of the dorso-lateral telencephalonThe boundary between Dld and Dlv is not clear. But the cells are more densely distributed in Dlv than Dld. The ventral part of the middle and posterior part of the dorso-lateral telencephalon (Dlv)(Anken and Bourrat, 1998) is highly packed with cells.DlpThe posterior regions of the dorso-lateral telencephalonHigher DAPI signal density in Dlp than Dld and Dlv were detected. There is no clear boundary among the posterior regions of the dorso-lateral telencephalon (Dlp), the posterior of dorsal telencephalon (Dp), Dld, and Dlv. But we observed that Dlp was highly dense with a small nucleus and the cell distribution pattern was different from neighboring regions.DdThe dorso-dorsal telencephalonIn the previous report (Anken and Bourrat, 1998), Dd is subdivided into two regions, Dd1 and Dd2. In the other report (Ishikawa et al., 1999), only Dd is defined which corresponds to Dd2 of Anken and Bourrat, 1998. Since the boundary between Dd1 and Dd2 was visible in DAPI staining, we followed the definition of Ralf H Anken, 1998.Dd1Dd2Dd2 is clearly demarcated in the telencephalon. As observed with the horizontal sections, Dd2 can be subdivided into two regions, Dd2a (anterior part of Dd2) and Dd2p (posterior part of Dd2). Dd2p is surrounded by cells, and the cell density is relatively higher than Dd2a.DpThe posterior part of dorsal telencephalonThe posterior part of dorsal telencephalon (Dp) (Anken and Bourrat, 1998) is remarkably denser with the cell nucleus than other posterior anatomical regions.VdThe dorsal medial part of the subpalliumCells in the dorsal medial part of the subpallium are called Vd. We also observed some cell clusters that are located laterally and inside the pallium. Those cell clusters correspond to the Vc region in some references. But according to the cell density and some gene expression, we define those regions also as Vd.VsThe supracommissural part of ventral telencephalonThe supracommissural part of ventral telencephalon (Vs) is located ventral to Vd. But there is no clear boundary between Vs and Vd.VvThe ventral part of the subpalliumECLThe external layer of the olfactory bulbIn the anterior part of the telencephalon, the external (ECL) and internal (ICL) cellular layer of the olfactory bulb and the glomerular layer of the olfactory bulb (GL) are clearly found.ICLThe internal layer of the olfactory bulb Video 1 Download asset This video cannot be played in place because your browser does support HTML5 video. You may still download the video for offline viewing. Download as MPEG-4 Download as WebM Download as Ogg Reference brain. DAPI-based reference brain. The slices show the horizontal view from the ventral to the dorsal direction. Next, to uncover the clonal architecture in the telencephalon, we genetically visualized the spatial distribution of cell lineages as previously established (Okuyama et al., 2013; Figure 1B). We used the transgenic line (Tg (HuC:loxp-DsRed-loxp-GFP)) that visualized neural progenitors by the HuC promoter, which labels 60–70% of all neurons in the adult telencephalon (Figure 1—figure supplement 2B). We crossed it to a second line (Tg (HSP-Cre)) that expresses Cre recombinase under the heat shock protein promoter. The Cre-loxp recombination was induced stochastically by heat shock at the neurula stage (stage 16–17; Iwamatsu, 2004) to visualize the progenitors derived from the same neural stem cells. We chose this developmental stage because the heat shock at an earlier developmental stage labeled to many neurons, and the heat shock at a later stage rarely induced recombination in our Tg line, which is presumably because of the positional effect of the insertion site in this transgenic line. Then, we cleared the adult brains with Scale solution, stained them with DAPI, and performed light-sheet microscope imaging. We first found that GFP-signal distributed differently between the pallium and subpallium; GFP-positive cell somas mixed with DsRed-positive cell somas in the subpallial regions (Figure 1Ci), while GFP-positive cells in the pallium formed exclusive compartments (Figure 1B, Videos 2 and 3). Video 2 Download asset This video cannot be played in place because your browser does support HTML5 video. You may still download the video for offline viewing. Download as MPEG-4 Download as WebM Download as Ogg Pallium. One of the examples of visualized clonally related units in the pallium (raw movie). GFP-positive cells (green) make a cluster and send a projection to the same site. Red signals indicate DsRed and blue signals indicate DAPI staining. The slices show the horizontal view from the dorsal to the ventral direction. Video 3 Download asset This video cannot be played in place because your browser does support HTML5 video. You may still download the video for offline viewing. Download as MPEG-4 Download as WebM Download as Ogg Subpallium. One of the examples of visualized clonally related units in the subpallium (raw movie). GFP-positive cells (green) and DsRed-positive cells (red) were mixed in the subpallial region. Blue signals indicate DAPI staining. The slices show the horizontal view from the dorsal to the ventral direction. For further investigation of the clonal architecture in each anatomical region, we analyzed the structure of the clonally related cells by applying a normalization method (Ostrovsky et al., 2013; Figure 1B). To that end, we registered the telencephalon of 81 medaka where 523 GFP-positive subpopulations were detected in total to a reference telencephalon. GFP-positive subpopulations that appeared multiple times in the same area were defined as clonally related units (Figure 1D). On average, we could visualize 6–8 units per fish (Figure 1—figure supplement 3A–C). We did not observe the GFP-positive units in a uniform frequency in the telencephalon, but more frequently in Dld, Dd2, and the subpallial regions than other areas (Figure 1—figure supplement 3C). We found the smallest clone in Dcpm, which included a few dozens of cells. We did not find any laterality of clonally related units, but we found more observed GFP-positive cells in the pallium than in the subpallium (Figure 1—figure supplement 3B–E). In the subpallium, we observed GFP-positive cells mixed with DsRed-positive cell with a 50% probability. On the other hand, most of the GFP-positive cells in the pallium were not mixed with DsRed-positive cells and did not locate across multiple regions (Figure 1—figure supplement 3F). For example, in the lateral pallium (Dl), the dorsal and ventral part of Dl were clearly different in terms of how the GFP-positive cell bodies are distributed (Figure 2B). Specifically, in the dorsal pallium, the anterior part (Dd2a) and the posterior part (Dd2p) consist of two clonally related units each that cluster laterally and medially, respectively. Taken together, we found that the anatomical regions in the pallium are formed by around 50 of the compartments of clonally related cell bodies, and the clonally related compartments distribute exclusively in one anatomical region but not across many anatomical regions. Figure 2 Download asset Open asset Neuronal projections of clonal units in the telencephalon. (A) Connectional matrix between clonal units in the telencephalon. The rows indicate the cell body locations and the columns indicate where the projection ends. The number of the projection among 81 fish we analyzed was normalized by the total number of clonal units observed and calculated as the ratio of projection, which is visualized in the color code. (B) The structure of clonal units in the telencephalon. We identified the structure of clonal units by systematic analysis, and here we visualized them in different colors that form a single anatomical region. The color of the outline of panels represents the color code of the anatomical regions, but the colors of each clonal unit inside each region are randomly assigned. In each anatomical brain region, the cell soma location and neural projections of clonal units are indicated by circles and line with a triangle terminal for each. For some clonal units where the registration of brains did not work well, we could not visualize the structure of clonal units in the reference brain. In these cases, we showed raw images of those clonal units. The cell-body distributions in the pallium and subpallium are consistent with the pattern of the neural stem cell (radial glial) (Figure 1—figure supplement 4). In the teleost telencephalon, the cell bodies of radial glia locate in the surface of the hemispheres and project inside the telencephalon (Dirian et al., 2014). Since neural progenitors migrate along those axons, it is consistent that the cell bodies of the pallial clonally related units are clustered along those axons in a cylindrical way. Cell lineages in the pallium tend to project to the same target regions We next asked whether individual members of cell lineages exhibit similar projection patterns or whether they target various regions. In Drosophila, clonal units project to the same target and work as connecting modules (Ito et al., 2013), whereas clonally related cells in the mammalian visual cortex tend to connect to each other but do not project to the same targets (Yu et al., 2012). To assess this question in teleosts, we traced the axonal projections of the cell lineages (Figure 2A). We found that, first, axons and dendrites from the cell lineages in the subpallium intermingled with each other, and they send brain-wide projections (Figure 2B). On the other hand, the pallial cell lineages sent axon bundles mostly to the same target region (Figure 2, Figure 1—figure supplement 3G). We also found several long connections: from the posterior area of the posterior part of dorsal telencephalon (Dp) to the contralateral hemisphere via the anterior commissure; from the anterior area of Dp and the ventral part of Dlv through Dc to Olfactory bulb. These long projections imply that this transgenic line labels both neural progenitors and young mature neurons at least in some brain regions. Further, we found many connections that project from and into the dorsal pallium (Dd2), which allow us to hypothesize a local pallial network around Dd2 (Figure 2B). Based on this observation that cell lineages in the pallium tend to project to the same target, we concluded that the labeled cellular subpopulations are clonal units. Distinct open chromatin structure in the medaka dorsal pallium (Dd2) The results enumerated above prompted us to hypothesize that gene expression is uniquely regulated in each clonal unit (Figure 3). In order to test this, we performed ATAC-seq on clonal units dissected from sliced brains to examine open chromatin regions (OCRs) that are either specific to or shared across the individually labeled clonal units (Figure 3A and B, Figure 3—figure supplement 1A and B). We generated ATAC-seq data from 100 sliced brain samples, and 65 samples met the criteria for screening high-quality data (see ‘Methods’; Figure 3C). To quantitatively test the relationship between the samples, we compared the ATAC-seq peak pattern (see ‘Methods’). Hierarchical clustering revealed that clonal units from the same brain regions tend to cluster together (Figure 3D). We then classified OCRs into 15 clusters (OCR Cs) by k-means clustering. We first found that OCR clusters specific in the subpallium (OCR C1-5) are distinct from OCR clusters specific in the pallial clonal units (OCR C6-13), which is reflected by their distinct gene expression from the early developmental stage (Mueller and Wullimann, 2009). Figure 3 with 1 supplement see all Download asset Open asset ATAC-seq of clonal units in the adult medaka telencephalon. (A) Procedure of ATAC-sequencing with extracted clonal units from the adult telencephalon. Cre-loxP recombination was induced at the neurula stage in the transgenic embryos (Tg (HSP-Cre) × Tg (HuC:loxP-DsRed-loxP-GFP)) as previously described. After making 130-um-thick brain slices at the adult stage, GFP-positive cellular subpopulations were dissected and extracted manually. (B) Examples of GFP-positive clonal units in the brain slices. White dotted lines indicate the outline of the brain slices. Green lines indicate the dissected GFP-positive clonal units. The ids of clonal-unit ATAC-seq samples are written next to the GFP-positive clonal units in each picture. (C) Representative track view of ATAC-seq. Colors of clonal units’ names indicate the location in the anatomical regions (Figure 1A) of the extracted clonal units. (D) Hierarchical clustering and k-means clustering of ATAC-seq peaks in clonal units. In the heatmap, blue indicates closed chromatin regions and yellow indicates open chromatin regions (OCR). Colors of clonal units’ names indicate the anatomical regions. (E) Dimensionality reduction analysis (tSNE) of ATAC-seq peak patterns of clonal units. Colors of clonal units’ names indicate the anatomical regions. A gray circle highlights the datapoints of clonal units of Dd1 and Dd2. Within the pallium, clonal units in the different subregions show unique patterns, where the medial and posterior pallium contained OCR C13 and OCR C8, respectively, and the ventral-lateral pallium (Dlv), the medial (Dlv-m), and posterior (Dlv-p) showed a variety of different OCRs (Figure 3D). Remarkably, the clonal units in the dorsal pallium (Dd2) were found to have distinct chromatin structure compared to all other clonal units in the telencephalon (Figure 3D); OCR C6 and 7 were specifically open in the genome of Dd2 samples, and other OCR clusters that are open in other pallial regions (e.g. C8-14) tended to be closed in Dd2. Dimensionality reduction methods, such as principal component analysis (PCA), tSNE, and Uniform Manifold Approximation and Projection (UMAP) analysis, confirmed that, apart from subpallial clonal units, clonal units in Dd2 were distant from other pallial cell lineages (Figure 3E, Figure 3—figure supplement 1C). We examined the distribution of ATAC-seq peaks in the genome, and Dd2-specific ATAC-seq peaks, located mainly in the intron and intergenic regions (Figure 3—figure supplement 1D), suggesting that the genomic regions that exhibit these peaks function as Dd2-specific enhancers. In summary, this ATAC-seq analysis suggests that the chromatin structures differ, depending on brain regions, and that it singles out the Dd2 region as an area of particularly distinct regulation. Enhanced transcriptional regulation on synaptic genes in Dd2 Next, to uncover which genes are differentially regulated in Dd2, we examined Gene Ontology (GO) term enrichment for genes targeted by each OCR cluster (Figure 4A). First, we found that the terms related to axon guidance and neurogenesis were enriched in various OCR clusters (Figure 4A, top; OCR C1, 3–7, 9, 12, and 14), which suggests that genes in the axon guidance pathways and neurogenesis are differentially regulated in different clonal units. Also, the GO terms related to early development were enriched in OCR cluster 14, and many metabolic and biosynthesis processes were enriched in OCR cluster 15. Also, one of the subpallial OCR clusters (OCR C5) was enriched with neu" @default.
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W4385234394 title "Author response: Epigenetically distinct synaptic architecture in clonal compartments in the teleostean dorsal pallium" @default.
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