scholarly journals A novel regulatory gene promotes novel cell fate by suppressing ancestral fate in the sea anemone Nematostella vectensis

2021 ◽  
Author(s):  
Leslie S Babonis ◽  
Camille Enjolras ◽  
Joseph F Ryan ◽  
Mark Q Martindale

AbstractCnidocytes (“stinging cells”) are an unequivocally novel cell type used by cnidarians (corals, jellyfish, and their kin) to immobilize prey. Although they are known to share a common evolutionary origin with neurons, the developmental program that promoted the emergence of cnidocyte fate is not known. Using functional genomics in the sea anemone, Nematostella vectensis, we show that cnidocytes evolved by suppression of neural fate in a subset of neurons expressing RFamide. We further show that a single regulatory gene, a C2H2-type zinc finger transcription factor (ZNF845), coordinates both the gain of novel (cnidocyte-specific) traits and the inhibition of ancestral (neural) traits during cnidocyte development and that this gene arose by domain shuffling in the stem cnidarian. Thus, we uncover a mechanism by which a truly novel regulatory gene (ZNF845) promoted the origin of a truly novel cell type (cnidocyte) through duplication of an ancestral cell lineage (neuron) and inhibition of its ancestral identity (RFamide).SignificanceIn this study, we demonstrate how new cell types can arise in animals through duplication of an ancestral (old) cell type followed by functional divergence of the new daughter cell. Specifically, we show that stinging cells in cnidarians (jellyfish and corals) evolved by duplication of an ancestral neuron followed by inhibition of the RFamide neuropeptide it once secreted. This is the first evidence that stinging cells evolved from a specific subtype of neurons and suggests some neurons may be easier to co-opt for novel functions than others.

2020 ◽  
Author(s):  
Alison G. Cole ◽  
Sabrina Kaul ◽  
Stefan M. Jahnel ◽  
Julia Steger ◽  
Bob Zimmerman ◽  
...  

AbstractThe 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.One Sentence SummaryThe study of the simple sea anemone suggests a molecular mechanism for cell type evolution and morphological complexity.


2020 ◽  
Author(s):  
Zhuoxin Chen ◽  
Chang Ye ◽  
Zhan Liu ◽  
Shanjun Deng ◽  
Xionglei He ◽  
...  

AbstractIt has been challenging to characterize the lineage relationships among cells in vertebrates, which comprise a great number of cells. Fortunately, recent progress has been made by combining the CRISPR barcoding system with single-cell sequencing technologies to provide an unprecedented opportunity to track lineage at single-cell resolution. However, due to errors and/or dropouts introduced by amplification and sequencing, reconstruction of accurate lineage relationships in complex organisms remains a challenge. Thus, improvements in both experimental design and computational analysis are necessary for lineage inference. In this study, we employed single-cell Lineage tracing On Endogenous Scarring Sites (scLOESS), a lineage recording strategy based on the CRISPR-Cas9 system, to trace cell fate commitments for zebrafish larvae. With rigorous quality control, we demonstrated that lineage commitments of complex organisms could be inferred from a limited number of barcoding sites. Together with cell-type characterization, our method could homogenously recover lineage information. In combination with the cell-type and lineage information, we depicted the development histories for germ layers as well as cell types. Furthermore, when combined with trajectory analysis, our methods could capture and resolve the ongoing lineage commitment events to gain further biological insights into later development and differentiation in complex organisms.


2021 ◽  
Author(s):  
Leslie S Babonis ◽  
Camille Enjolras ◽  
Abigail J Reft ◽  
Brent M Foster ◽  
Fredrik Hugosson ◽  
...  

Cnidocytes are the explosive stinging cells found only in cnidarians (corals, jellyfish, etc). Specialized for prey capture and defense, cnidocytes are morphologically complex and vary widely in form and function across taxa; how such diversity evolved is unknown. Using CRISPR/Cas9-mediated genome editing in the burrowing sea anemone Nematostella vectensis, we show that a single transcription factor (NvSox2) acts as a binary switch between two alternative cnidocyte fates. Knockout of NvSox2 caused a complete transformation of nematocytes (piercing cells) into spirocytes (ensnaring cells). The type of spirocyte induced by NvSox2 knockout (robust spirocyte) is not normally found in N. vectensis but is common in sea anemones from other habitats. Homeotic control of cell fate provides a mechanistic explanation for the discontinuous distribution of cnidocyte types across cnidarians and demonstrates how simple counts of cell types can underestimate biodiversity.


2020 ◽  
Author(s):  
Manuela Wuelling ◽  
Christoph Neu ◽  
Andrea M. Thiesen ◽  
Simo Kitanovski ◽  
Yingying Cao ◽  
...  

AbstractEpigenetic modifications play critical roles in regulating cell lineage differentiation, but the epigenetic mechanisms guiding specific differentiation steps within a cell lineage have rarely been investigated. To decipher such mechanisms, we used the defined transition from proliferating (PC) into hypertrophic chondrocytes (HC) during endochondral ossification as a model. We established a map of activating and repressive histone modifications for each cell type. ChromHMM state transition analysis and Pareto-based integration of differential levels of mRNA and epigenetic marks revealed that differentiation associated gene repression is initiated by the addition of H3K27me3 to promoters still carrying substantial levels of activating marks. Moreover, the integrative analysis identified genes specifically expressed in cells undergoing the transition into hypertrophy.Investigation of enhancer profiles detected surprising differences in enhancer number, location, and transcription factor binding sites between the two closely related cell types. Furthermore, cell type-specific upregulation of gene expression was associated with a shift from low to high H3K27ac decoration. Pathway analysis identified PC-specific enhancers associated with chondrogenic genes, while HC-specific enhancers mainly control metabolic pathways linking epigenetic signature to biological functions.


2019 ◽  
Author(s):  
Alexandra Grubman ◽  
Gabriel Chew ◽  
John F. Ouyang ◽  
Guizhi Sun ◽  
Xin Yi Choo ◽  
...  

AbstractAlzheimer’s disease (AD) is a heterogeneous disease that is largely dependent on the complex cellular microenvironment in the brain. This complexity impedes our understanding of how individual cell types contribute to disease progression and outcome. To characterize the molecular and functional cell diversity in the human AD brain we utilized single nuclei RNA- seq in AD and control patient brains in order to map the landscape of cellular heterogeneity in AD. We detail gene expression changes at the level of cells and cell subclusters, highlighting specific cellular contributions to global gene expression patterns between control and Alzheimer’s patient brains. We observed distinct cellular regulation of APOE which was repressed in oligodendrocyte progenitor cells (OPCs) and astrocyte AD subclusters, and highly enriched in a microglial AD subcluster. In addition, oligodendrocyte and microglia AD subclusters show discordant expression of APOE. Integration of transcription factor regulatory modules with downstream GWAS gene targets revealed subcluster-specific control of AD cell fate transitions. For example, this analysis uncovered that astrocyte diversity in AD was under the control of transcription factor EB (TFEB), a master regulator of lysosomal function and which initiated a regulatory cascade containing multiple AD GWAS genes. These results establish functional links between specific cellular sub-populations in AD, and provide new insights into the coordinated control of AD GWAS genes and their cell-type specific contribution to disease susceptibility. Finally, we created an interactive reference web resource which will facilitate brain and AD researchers to explore the molecular architecture of subtype and AD-specific cell identity, molecular and functional diversity at the single cell level.HighlightsWe generated the first human single cell transcriptome in AD patient brainsOur study unveiled 9 clusters of cell-type specific and common gene expression patterns between control and AD brains, including clusters of genes that present properties of different cell types (i.e. astrocytes and oligodendrocytes)Our analyses also uncovered functionally specialized sub-cellular clusters: 5 microglial clusters, 8 astrocyte clusters, 6 neuronal clusters, 6 oligodendrocyte clusters, 4 OPC and 2 endothelial clusters, each enriched for specific ontological gene categoriesOur analyses found manifold AD GWAS genes specifically associated with one cell-type, and sets of AD GWAS genes co-ordinately and differentially regulated between different brain cell-types in AD sub-cellular clustersWe mapped the regulatory landscape driving transcriptional changes in AD brain, and identified transcription factor networks which we predict to control cell fate transitions between control and AD sub-cellular clustersFinally, we provide an interactive web-resource that allows the user to further visualise and interrogate our dataset.Data resource web interface:http://adsn.ddnetbio.com


2021 ◽  
Author(s):  
Jinyue Liao ◽  
Hoi Ching Suen ◽  
Shitao Rao ◽  
Alfred Chun Shui Luk ◽  
Ruoyu Zhang ◽  
...  

AbstractSpermatogenesis depends on an orchestrated series of developing events in germ cells and full maturation of the somatic microenvironment. To date, the majority of efforts to study cellular heterogeneity in testis has been focused on single-cell gene expression rather than the chromatin landscape shaping gene expression. To advance our understanding of the regulatory programs underlying testicular cell types, we analyzed single-cell chromatin accessibility profiles in more than 25,000 cells from mouse developing testis. We showed that scATAC-Seq allowed us to deconvolve distinct cell populations and identify cis-regulatory elements (CREs) underlying cell type specification. We identified sets of transcription factors associated with cell type-specific accessibility, revealing novel regulators of cell fate specification and maintenance. Pseudotime reconstruction revealed detailed regulatory dynamics coordinating the sequential developmental progressions of germ cells and somatic cells. This high-resolution data also revealed putative stem cells within the Sertoli and Leydig cell populations. Further, we defined candidate target cell types and genes of several GWAS signals, including those associated with testosterone levels and coronary artery disease. Collectively, our data provide a blueprint of the ‘regulon’ of the mouse male germline and supporting somatic cells.


2016 ◽  
Author(s):  
Enrique Carrillo-de-Santa-Pau ◽  
David Juan ◽  
Vera Pancaldi ◽  
Felipe Were ◽  
Ignacio Martin-Subero ◽  
...  

AbstractHematopoiesis is one of the best characterized biological systems but the connection between chromatin changes and lineage differentiation is not yet well understood. We have developed a bioinformatic workflow to generate a chromatin space that allows to classify forty-two human healthy blood epigenomes from the BLUEPRINT, NIH ROADMAP and ENCODE consortia by their cell type. This approach let us to distinguish different cells types based on their epigenomic profiles, thus recapitulating important aspects of human hematopoiesis. The analysis of the orthogonal dimension of the chromatin space identify 32,662 chromatin determinant regions (CDRs), genomic regions with different epigenetic characteristics between the cell types. Functional analysis revealed that these regions are linked with cell identities. The inclusion of leukemia epigenomes in the healthy hematological chromatin sample space gives us insights on the healthy cell types that are more epigenetically similar to the disease samples. Further analysis of tumoral epigenetic alterations in hematopoietic CDRs points to sets of genes that are tightly regulated in leukemic transformations and commonly mutated in other tumors. Our method provides an analytical approach to study the relationship between epigenomic changes and cell lineage differentiation. Method availability: https://github.com/david-juan/ChromDet


2021 ◽  
Vol 22 (18) ◽  
pp. 9667
Author(s):  
Geoffrey Brown

In principle, an oncogene is a cellular gene (proto-oncogene) that is dysfunctional, due to mutation and fusion with another gene or overexpression. Generally, oncogenes are viewed as deregulating cell proliferation or suppressing apoptosis in driving cancer. The cancer stem cell theory states that most, if not all, cancers are a hierarchy of cells that arises from a transformed tissue-specific stem cell. These normal counterparts generate various cell types of a tissue, which adds a new dimension to how oncogenes might lead to the anarchic behavior of cancer cells. It is that stem cells, such as hematopoietic stem cells, replenish mature cell types to meet the demands of an organism. Some oncogenes appear to deregulate this homeostatic process by restricting leukemia stem cells to a single cell lineage. This review examines whether cancer is a legacy of stem cells that lose their inherent versatility, the extent that proto-oncogenes play a role in cell lineage determination, and the role that epigenetic events play in regulating cell fate and tumorigenesis.


Development ◽  
1998 ◽  
Vol 125 (23) ◽  
pp. 4645-4654 ◽  
Author(s):  
J. Adam ◽  
A. Myat ◽  
I. Le Roux ◽  
M. Eddison ◽  
D. Henrique ◽  
...  

The sensory patches in the vertebrate inner ear are similar in function to the mechanosensory bristles of a fly, and consist of a similar set of cell types. If they are truly homologous structures, they should also develop by similar mechanisms. We examine the genesis of the neurons, hair cells and supporting cells that form the sensory patches in the inner ear of the chick. These all arise from the otic epithelium, and are produced normally even in otic epithelium cultured in isolation, confirming that their production is governed by mechanisms intrinsic to the epithelium. First, the neuronal sublineage becomes separate from the epithelial: between E2 and E3.5, neuroblasts delaminate from the otocyst. The neuroblasts then give rise to a mixture of neurons and neuroblasts, while the sensory epithelial cells diversify to form a mixture of hair cells and supporting cells. The epithelial patches where this occurs are marked from an early stage by uniform and maintained expression of the Notch ligand Serrate1. The Notch ligand Delta1 is also expressed, but transiently and in scattered cells: it is seen both early, during neuroblast segregation, where it appears to be in the nascent neuroblasts, and again later, in the ganglion and in differentiating sensory patches, where it appears to be in the nascent hair cells, disappearing as they mature. Delta-Notch-mediated lateral inhibition may thus act at each developmental branchpoint to drive neighbouring cells along different developmental pathways. Our findings indicate that the sensory patches of the vertebrate inner ear and the sensory bristles of a fly are generated by minor variations of the same basic developmental program, in which cell diversification driven by Delta-Notch and/or Serrate-Notch signalling plays a central part.


Development ◽  
1995 ◽  
Vol 121 (10) ◽  
pp. 3175-3185 ◽  
Author(s):  
M.Q. Martindale ◽  
J.Q. Henry

The nemerteans belong to a phylum of coelomate worms that display a highly conserved pattern of cell divisions referred to as spiral cleavage. It has recently been shown that the fates of the four embryonic cell quadrants in two species of nemerteans are not homologous to those in other spiralian embryos, such as the annelids and molluscs (Henry, J. Q. and Martindale, M. Q. (1994a) Develop. Genetics 15, 64–78). Equal-cleaving molluscs utilize inductive interactions to establish quadrant-specific cell fates and embryonic symmetry properties following fifth cleavage. In order to elucidate the manner in which cell fates are established in nemertean embryos, we have conducted cell isolation and deletion experiments to examine the developmental potential of the early cleavage blastomeres of two equal-cleaving nemerteans, Nemertopsis bivittata and Cerebratulus lacteus. These two species display different modes of development: N. bivittata develops directly via a non-feeding larvae, while C. lacteus develops to form a feeding pilidium larva which undergoes a radical metamorphosis to give rise to the juvenile worm. By examining the development of certain structures and cell types characteristic of quadrant-specific fates for each of these species, we have shown that isolated blastomeres of the indirect-developing nemertean, C. lacteus, are capable of generating cell fates that are not a consequence of that cell's normal developmental program. For instance, dorsal blastomeres can form muscle fibers when cultured in isolation. In contrast, isolated blastomeres of the direct-developing species, N. bivittata do not regulate their development to the same extent. Some cell fates are specified in a precocious manner in this species, such as those that give rise to the eyes. Thus, these findings indicate that equal-cleaving spiralian embryos can utilize different mechanisms of cell fate and axis specification. The implications of these patterns of nemertean development are discussed in relation to experimental work in other spiralian embryos, and a model is presented that accounts for possible evolutionary changes in cell lineage and the process of cell fate specification amongst these protostome phyla.


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