scholarly journals Modeling of histone modifications reveals formation mechanism and function of bivalent chromatin

2021 ◽  
Author(s):  
Wei Zhao ◽  
Lingxia Qiao ◽  
Shiyu Yan ◽  
Qing Nie ◽  
Lei Zhang
Keyword(s):  
Cell Fate ◽  
Histone Modifications ◽  
Necessary Conditions ◽  
Chromatin State ◽  
Chromatin Domain ◽  
Biological Processes ◽  
Cell Fate Determination ◽  
Repressive Chromatin ◽  
And Function ◽  
Bivalent Chromatin Domain

AbstractBivalent chromatin is characterized by occupation of both activating histone modifications and repressive histone modifications. While bivalent chromatin is known to link with many biological processes, the mechanisms responsible for its multiple functions remain unclear. Here, we develop a mathematical model that involves antagonistic histone modifications H3K4me3 and H3K27me3 to capture the key features of bivalent chromatin. Three necessary conditions for the emergence of bivalent chromatin are identified, including advantageous methylating activity over demethylating activity, frequent noise conversions of modifications, and sufficient nonlinearity. The first condition is further confirmed by analyzing the experimental data from a recent study. Investigation of the composition of bivalent chromatin reveals that bivalent nucleosomes carrying both H3K4me3 and H3K27me3 account for no more than half of nucleosomes at the bivalent chromatin domain. We identify that bivalent chromatin not only allows transitions to multiple states but also serves as a stepping stone to facilitate a step-wise transition between repressive chromatin state and activating chromatin state, and thus elucidate crucial roles of bivalent chromatin in mediating phenotypical plasticity during cell fate determination.

scholarly journals The Chromatin State during Gonadal Sex Determination

2021 ◽  
pp. 1-9
Author(s):  
Shannon Dupont ◽  
Blanche Capel
Keyword(s):  
Sex Determination ◽  
Cell Fate ◽  
Granulosa Cell ◽  
Histone Modifications ◽  
Granulosa Cells ◽  
Gonad Development ◽  
Chromatin State ◽  
Supporting Cells ◽  
Direct Role ◽  
Specific Factors

At embryonic day (E) 10.5, prior to gonadal sex determination, XX and XY gonads are bipotential and able to differentiate into either a testis or an ovary. At this point, they are transcriptionally and morphologically indistinguishable. Sex determination begins around E11.5 in the mouse when the supporting cell lineage commits to either Sertoli or granulosa cell fate. Testis-specific factors such as SRY and SOX9 drive differentiation of bipotential-supporting cells into the Sertoli cell pathway, whereas ovary-specific factors like WNT4 and FOXL2 guide differentiation into granulosa cells. It is known that these 2 pathways are mutually antagonistic, and repression of the alternative fate is critical for maintenance of the testis or ovary programs. While we understand much about the transcription factor networks guiding the process of sex determination, it is only more recently that we have begun to understand how this process is epigenetically controlled. Studies in the past decade have demonstrated the importance of the chromatin state for gene expression and cell fate commitment, with histone modifications and DNA accessibility having a direct role in gene regulation. It is now clear that the chromatin state during sex determination is dynamic and likely critical for the establishment and/or maintenance of the transcriptional programs. Prior to sex determination, supporting cells have similar chromatin structure and histone modification profiles, reflecting the bipotential nature of these cells. After differentiation to Sertoli or granulosa cells, the chromatin state acquires sex-specific profiles. The proteins that regulate the deposition of histone modifications or the opening of compact chromatin likely play an important role in Sertoli and granulosa cell fate commitment and gonad development. Here, we describe studies profiling the chromatin state during gonadal sex determination and one example in which depletion of <i>Cbx2</i>, a member of the Polycomb Repressive Complex 1 (PRC1), causes male-to-female sex reversal due to a failure to repress the ovarian pathway.

scholarly journals Smek1/2 is a nuclear chaperone and cofactor for cleaved Wnt receptor Ryk, regulating cortical neurogenesis

2017 ◽  
Vol 114 (50) ◽  
pp. E10717-E10725 ◽  
Author(s):  
Wen-Hsuan Chang ◽  
Si Ho Choi ◽  
Byoung-San Moon ◽  
Mingyang Cai ◽  
Jungmook Lyu ◽  
...  
Keyword(s):  
Neuronal Differentiation ◽  
Cell Fate ◽  
Cortical Neurons ◽  
Nuclear Translocation ◽  
Stem Cell Population ◽  
Cell Fate Determination ◽  
Double Knockout ◽  
Gene Transcription Regulation ◽  
And Function ◽  
Neural Cell Fate

The receptor-like tyrosine kinase (Ryk), a Wnt receptor, is important for cell fate determination during corticogenesis. During neuronal differentiation, the Ryk intracellular domain (ICD) is cleaved. Cleavage of Ryk and nuclear translocation of Ryk-ICD are required for neuronal differentiation. However, the mechanism of translocation and how it regulates neuronal differentiation remain unclear. Here, we identified Smek1 and Smek2 as Ryk-ICD partners that regulate its nuclear localization and function together with Ryk-ICD in the nucleus through chromatin recruitment and gene transcription regulation. Smek1/2 double knockout mice displayed pronounced defects in the production of cortical neurons, especially interneurons, while the neural stem cell population increased. In addition, both Smek and Ryk-ICD bound to the Dlx1/2 intergenic regulator element and were involved in its transcriptional regulation. These findings demonstrate a mechanism of the Ryk signaling pathway in which Smek1/2 and Ryk-ICD work together to mediate neural cell fate during corticogenesis.

scholarly journals RNA methylation in mammalian development and cancer

2021 ◽  
Author(s):  
Peizhe Song ◽  
Subiding Tayier ◽  
Zhihe Cai ◽  
Guifang Jia
Keyword(s):  
Cell Fate ◽  
Cancer Progression ◽  
Rna Modification ◽  
Biological Processes ◽  
Cell Fate Determination ◽  
Mammalian Development ◽  
Rna Modifications ◽  
Temporal And Spatial ◽  
Underlying Mechanisms ◽  
Cellular Components

AbstractSimilar to epigenetic DNA and histone modifications, epitranscriptomic modifications (RNA modifications) have emerged as crucial regulators in temporal and spatial gene expression during eukaryotic development. To date, over 170 diverse types of chemical modifications have been identified upon RNA nucleobases. Some of these post-synthesized modifications can be reversibly installed, removed, and decoded by their specific cellular components and play critical roles in different biological processes. Accordingly, dysregulation of RNA modification effectors is tightly orchestrated with developmental processes. Here, we particularly focus on three well-studied RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), and N1-methyladenosine (m1A), and summarize recent knowledge of underlying mechanisms and critical roles of these RNA modifications in stem cell fate determination, embryonic development, and cancer progression, providing a better understanding of the whole association between epitranscriptomic regulation and mammalian development.

Carboxypeptidase A5 identifies a novel mast cell lineage in the zebrafish providing new insight into mast cell fate determination

Blood ◽  
2008 ◽  
Vol 112 (7) ◽  
pp. 2969-2972 ◽  
Author(s):  
J. Tristan Dobson ◽  
Jake Seibert ◽  
Evelyn M. Teh ◽  
Sahar Da'as ◽  
Robert B. Fraser ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Fate ◽  
Cell Lineage ◽  
Cell Fate Determination ◽  
Specific Enzyme ◽  
Efficient System ◽  
And Function ◽  
Insight Into ◽  
Lysozyme C

Abstract Mast cells (MCs) play critical roles in allergy and inflammation, yet their development remains controversial due to limitations posed by traditional animal models. The zebrafish provides a highly efficient system for studying vertebrate hematopoiesis. We have identified zebrafish MCs in the gill and intestine, which resemble their mammalian counterparts both structurally and functionally. Carboxypeptidase A5 (cpa5), a MC-specific enzyme, is expressed in zebrafish blood cells beginning at 24 hours post fertilization (hpf). At 28 hpf, colocalization is observed with pu.1, mpo, l-plastin, and lysozyme C, but not fms or cepbα, identifying these early MCs as a distinct myeloid population arising from a common granulocyte/monocyte progenitor. Morpholino “knock-down” studies demonstrate that transcription factors gata-2 and pu.1, but not gata-1 or fog-1, are necessary for early MC development. These studies validate the zebrafish as an in vivo tool for studying MC ontogeny and function with future capacity for modeling human MC diseases.

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