Cellular identity and lineage choice

DNA replication timing (RT), reflecting the temporal order of origin activation, is known as a robust and conserved cell-type specific process. Upon low replication stress, the slowing of replication forks induces well-documented RT delays associated to genetic instability, but it can also generate RT advances that are still uncharacterized. In order to characterize these advanced initiation events, we monitored the whole genome RT from six independent human cell lines treated with low doses of aphidicolin. We report that RT advances are cell-type-specific and involve large heterochromatin domains. Importantly, we found that some major late to early RT advances can be inherited by the unstressed next-cellular generation, which is a unique process that correlates with enhanced chromatin accessibility, as well as modified replication origin landscape and gene expression in daughter cells. Collectively, this work highlights how low replication stress may impact cellular identity by RT advances events at a subset of chromosomal domains.

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A generalization of t-SNE and UMAP to single-cell multimodal omics

Genome Biology ◽

10.1186/s13059-021-02356-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Van Hoan Do ◽

Stefan Canzar

Keyword(s):

Dimensionality Reduction ◽

Single Cell ◽

Cell Types ◽

High Dimensional ◽

Omics Data ◽

Relative Contribution ◽

Reduction Techniques ◽

Dimensionality Reduction Techniques ◽

Concise Representation ◽

Cellular Identity

AbstractEmerging single-cell technologies profile multiple types of molecules within individual cells. A fundamental step in the analysis of the produced high-dimensional data is their visualization using dimensionality reduction techniques such as t-SNE and UMAP. We introduce j-SNE and j-UMAP as their natural generalizations to the joint visualization of multimodal omics data. Our approach automatically learns the relative contribution of each modality to a concise representation of cellular identity that promotes discriminative features but suppresses noise. On eight datasets, j-SNE and j-UMAP produce unified embeddings that better agree with known cell types and that harmonize RNA and protein velocity landscapes.

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Characterizing Cellular Identity at One Cell Resolution

In Situ Hybridization Methods - Neuromethods ◽

10.1007/978-1-4939-2303-8_28 ◽

2015 ◽

pp. 541-548

Author(s):

Amaresh K. Ranjan ◽

Mugdha V. Joglekar ◽

Anandwardhan A. Hardikar

Keyword(s):

Cellular Identity

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Phospho-Tau and Chromatin Landscapes in Early and Late Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms221910283 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10283

Author(s):

Laura Gil ◽

Sandra A. Niño ◽

Carmen Guerrero ◽

María E. Jiménez-Capdeville

Keyword(s):

Gene Expression ◽

Tau Protein ◽

Pyramidal Neurons ◽

Genomic Stability ◽

Dynamic Structure ◽

Histone Code ◽

Chromatin Interaction ◽

Cancer Phenotype ◽

Cellular Identity ◽

Cellular Transformations

Cellular identity is determined through complex patterns of gene expression. Chromatin, the dynamic structure containing genetic information, is regulated through epigenetic modulators, mainly by the histone code. One of the main challenges for the cell is maintaining functionality and identity, despite the accumulation of DNA damage throughout the aging process. Replicative cells can remain in a senescent state or develop a malign cancer phenotype. In contrast, post-mitotic cells such as pyramidal neurons maintain extraordinary functionality despite advanced age, but they lose their identity. This review focuses on tau, a protein that protects DNA, organizes chromatin, and plays a crucial role in genomic stability. In contrast, tau cytosolic aggregates are considered hallmarks of Alzheimer´s disease (AD) and other neurodegenerative disorders called tauopathies. Here, we explain AD as a phenomenon of chromatin dysregulation directly involving the epigenetic histone code and a progressive destabilization of the tau–chromatin interaction, leading to the consequent dysregulation of gene expression. Although this destabilization could be lethal for post-mitotic neurons, tau protein mediates profound cellular transformations that allow for their temporal survival.

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Notch family members follow stringent requirements for intracellular domain dimerization at sequence-paired sites

10.1101/2020.05.20.106054 ◽

2020 ◽

Author(s):

Jacob J. Crow ◽

Allan R. Albig

Keyword(s):

Transcriptional Activation ◽

Target Genes ◽

Regulatory Mechanism ◽

Family Members ◽

Regulatory Function ◽

Specific Nature ◽

Intracellular Domain ◽

Notch Intracellular Domain ◽

Highly Sensitive ◽

Cellular Identity

ABSTRACTNotch signaling is essential for multicellular life, regulating core functions such as cellular identity, differentiation, and fate. These processes require highly sensitive systems to avoid going awry, and one such regulatory mechanism is through Notch intracellular domain dimerization. Select Notch target genes contain sequence-paired sites (SPS); motifs in which two Notch transcriptional activation complexes can bind and interact through Notch’s ankyrin domain, resulting in enhanced transcriptional activation. This mechanism has been mostly studied through Notch1, and to date, the abilities of the other Notch family members have been left unexplored. Through the utilization of minimalized, SPS-driven luciferase assays, we were able to test the functional capacity of Notch dimers. Here we show that each family member is capable of dimerization-induced signaling, following the same stringent requirements as seen with Notch1. Interestingly, we identified a mechanical difference between canonical and cryptic SPSs, leading to differences in their dimerization-induced regulation. Finally, we profiled the Notch family members’ SPS gap distance preferences and found that they all prefer a 16-nucleotide gap, with little room for variation. In summary, this work highlights the potent and highly specific nature of Notch dimerization and refines the scope of this regulatory function.

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Cbx2 stably associates with mitotic chromosomes via a PRC2- or PRC1-independent mechanism and is needed for recruiting PRC1 complex to mitotic chromosomes

Molecular Biology of the Cell ◽

10.1091/mbc.e14-06-1109 ◽

2014 ◽

Vol 25 (23) ◽

pp. 3726-3739 ◽

Cited By ~ 23

Author(s):

Chao Yu Zhen ◽

Huy Nguyen Duc ◽

Marko Kokotovic ◽

Christopher J. Phiel ◽

Xiaojun Ren

Keyword(s):

Molecular Mechanisms ◽

Es Cells ◽

Epigenetic Inheritance ◽

Polycomb Group ◽

Mitotic Chromosomes ◽

Mouse Es Cells ◽

C Terminus ◽

Independent Mechanism ◽

Cellular Identity ◽

Quantitative Fluorescence

Polycomb group (PcG) proteins are epigenetic transcriptional factors that repress key developmental regulators and maintain cellular identity through mitosis via a poorly understood mechanism. Using quantitative live-cell imaging in mouse ES cells and tumor cells, we demonstrate that, although Polycomb repressive complex (PRC) 1 proteins (Cbx-family proteins, Ring1b, Mel18, and Phc1) exhibit variable capacities of association with mitotic chromosomes, Cbx2 overwhelmingly binds to mitotic chromosomes. The recruitment of Cbx2 to mitotic chromosomes is independent of PRC1 or PRC2, and Cbx2 is needed to recruit PRC1 complex to mitotic chromosomes. Quantitative fluorescence recovery after photobleaching analysis indicates that PRC1 proteins rapidly exchange at interphasic chromatin. On entry into mitosis, Cbx2, Ring1b, Mel18, and Phc1 proteins become immobilized at mitotic chromosomes, whereas other Cbx-family proteins dynamically bind to mitotic chromosomes. Depletion of PRC1 or PRC2 protein has no effect on the immobilization of Cbx2 on mitotic chromosomes. We find that the N-terminus of Cbx2 is needed for its recruitment to mitotic chromosomes, whereas the C-terminus is required for its immobilization. Thus these results provide fundamental insights into the molecular mechanisms of epigenetic inheritance.

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