cellular differentiation
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Blood ◽  
2022 ◽  
Leif Ludwig ◽  
Caleb A Lareau ◽  
Erik L. Bao ◽  
Nan Liu ◽  
Taiju Utsugisawa ◽  

Master regulators, such as the hematopoietic transcription factor (TF) GATA1, play an essential role in orchestrating lineage commitment and differentiation. However, the precise mechanisms by which such TFs regulate transcription through interactions with specific cis-regulatory elements remain incompletely understood. Here, we describe a form of congenital hemolytic anemia caused by missense mutations in an intrinsically disordered region of GATA1, with a poorly understood role in transcriptional regulation. Through integrative functional approaches, we demonstrate that these mutations perturb GATA1 transcriptional activity by partially impairing nuclear localization and selectively altering precise chromatin occupancy by GATA1. These alterations in chromatin occupancy and concordant chromatin accessibility changes alter faithful gene expression, with failure to both effectively silence and activate select genes necessary for effective terminal red cell production. We demonstrate how disease-causing mutations can reveal regulatory mechanisms that enable the faithful genomic targeting of master TFs during cellular differentiation.

BMC Genomics ◽  
2022 ◽  
Vol 23 (1) ◽  
David J. Wright ◽  
Nicola A. L. Hall ◽  
Naomi Irish ◽  
Angela L. Man ◽  
Will Glynn ◽  

Abstract Background Alternative splicing is a key mechanism underlying cellular differentiation and a driver of complexity in mammalian neuronal tissues. However, understanding of which isoforms are differentially used or expressed and how this affects cellular differentiation remains unclear. Long read sequencing allows full-length transcript recovery and quantification, enabling transcript-level analysis of alternative splicing processes and how these change with cell state. Here, we utilise Oxford Nanopore Technologies sequencing to produce a custom annotation of a well-studied human neuroblastoma cell line SH-SY5Y, and to characterise isoform expression and usage across differentiation. Results We identify many previously unannotated features, including a novel transcript of the voltage-gated calcium channel subunit gene, CACNA2D2. We show differential expression and usage of transcripts during differentiation identifying candidates for future research into state change regulation. Conclusions Our work highlights the potential of long read sequencing to uncover previously unknown transcript diversity and mechanisms influencing alternative splicing.

Georgios Konstantinidis ◽  
Nektarios Tavernarakis

Nucleophagy is an organelle-selective subtype of autophagy that targets nuclear material for degradation. The macroautophagic delivery of micronuclei to the vacuole, together with the nucleus-vacuole junction-dependent microautophagic degradation of nuclear material, were first observed in yeast. Nuclear pore complexes and ribosomal DNA are typically excluded during conventional macronucleophagy and micronucleophagy, indicating that degradation of nuclear cargo is tightly regulated. In mammals, similarly to other autophagy subtypes, nucleophagy is crucial for cellular differentiation and development, in addition to enabling cells to respond to various nuclear insults and cell cycle perturbations. A common denominator of all nucleophagic processes characterized in diverse organisms is the dependence on the core autophagic machinery. Here, we survey recent studies investigating the autophagic processing of nuclear components. We discuss nucleophagic events in the context of pathology, such as neurodegeneration, cancer, DNA damage, and ageing.

Cell ◽  
2022 ◽  
Vol 185 (1) ◽  
pp. 145-157.e13
Kwang-Tao Chou ◽  
Dong-yeon D. Lee ◽  
Jian-geng Chiou ◽  
Leticia Galera-Laporta ◽  
San Ly ◽  

2021 ◽  
Umakant Yadav

Three-dimensional (3D) bioprinting is an emerging technology for fabricating cells, biomaterials and extracellular matrix (ECM) into customized shapes and patterns. Here, we report additive manufacturing to create a customized 3D bioactive constructs for regenerative medicine. We have attempted to emphasize the use of agarose and graphene oxide as a promising material for the conceptualization of bioink unpaid to its unique physicochemical properties. The 3D printed structure is able to regenerating bone tissues and regulates the cellular differentiation without any significant morphological changes. The presence of graphene oxide enhances the osteoinductive behavior of the developed scaffolds, which is further supplemented by encapsulating human mesenchymal stem cells (hMSCs) on the 3D printed scaffolds. A significant enhanced expression of early osteogenic markers like morphogenetic protein (BMP), Runx-2, collagen-1, osteopontin, osteocalcin as well as mineralized ECM are observed on agarose-hydroxyapatite and graphene oxide 3D printed scaffolds compared to agarose-hydroxyapatite 3D printed scaffolds. Thus, the outcomes of the developed 3D bioprinted scaffolds provide a promising strategy for development of personalized bone grafts for tissue regeneration.

2021 ◽  
Vol 118 (49) ◽  
pp. e2105859118
Chen Qiao ◽  
Yuanhua Huang

RNA velocity is a promising technique for quantifying cellular transitions from single-cell transcriptome experiments and revealing transient cellular dynamics among a heterogeneous cell population. However, the cell transitions estimated from high-dimensional RNA velocity are often unstable or inaccurate, partly due to the high technical noise and less informative projection. Here, we present Velocity Autoencoder (VeloAE), a tailored representation learning method, to learn a low-dimensional representation of RNA velocity on which cellular transitions can be robustly estimated. On various experimental datasets, we show that VeloAE can both accurately identify stimulation dynamics in time-series designs and effectively capture expected cellular differentiation in different biological systems. VeloAE, therefore, enhances the usefulness of RNA velocity for studying a wide range of biological processes.

2021 ◽  
Vol 11 (12) ◽  
Ryan J. Stubbins ◽  
Aly Karsan

AbstractBlocked cellular differentiation is a central pathologic feature of the myeloid malignancies, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Treatment regimens promoting differentiation have resulted in incredible cure rates in certain AML subtypes, such as acute promyelocytic leukemia. Over the past several years, we have seen many new therapies for MDS/AML enter clinical practice, including epigenetic therapies (e.g., 5-azacitidine), isocitrate dehydrogenase (IDH) inhibitors, fms-like kinase 3 (FLT3) inhibitors, and lenalidomide for deletion 5q (del5q) MDS. Despite not being developed with the intent of manipulating differentiation, induction of differentiation is a major mechanism by which several of these novel agents function. In this review, we examine the new therapeutic landscape for these diseases, focusing on the role of hematopoietic differentiation and the impact of inflammation and aging. We review how current therapies in MDS/AML promote differentiation as a part of their therapeutic effect, and the cellular mechanisms by which this occurs. We then outline potential novel avenues to achieve differentiation in the myeloid malignancies for therapeutic purposes. This emerging body of knowledge about the importance of relieving differentiation blockade with anti-neoplastic therapies is important to understand how current novel agents function and may open avenues to developing new treatments that explicitly target cellular differentiation. Moving beyond cytotoxic agents has the potential to open new and unexpected avenues in the treatment of myeloid malignancies, hopefully providing more efficacy with reduced toxicity.

2021 ◽  
Vol 12 (1) ◽  
Yoshihiro Matsumura ◽  
Ryo Ito ◽  
Ayumu Yajima ◽  
Rei Yamaguchi ◽  
Toshiya Tanaka ◽  

AbstractEnhancer activation is essential for cell-type specific gene expression during cellular differentiation, however, how enhancers transition from a hypoacetylated “primed” state to a hyperacetylated-active state is incompletely understood. Here, we show SET domain-containing 5 (SETD5) forms a complex with NCoR-HDAC3 co-repressor that prevents histone acetylation of enhancers for two master adipogenic regulatory genes Cebpa and Pparg early during adipogenesis. The loss of SETD5 from the complex is followed by enhancer hyperacetylation. SETD5 protein levels were transiently increased and rapidly degraded prior to enhancer activation providing a mechanism for the loss of SETD5 during the transition. We show that induction of the CDC20 co-activator of the ubiquitin ligase leads to APC/C mediated degradation of SETD5 during the transition and this operates as a molecular switch that facilitates adipogenesis.

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 456-456
Navdeep Chandel

Abstract The major function of mitochondria in cellular homeostasis has been the generation of ATP through oxidative phosphorylation. However, we have previously demonstrated that mitochondria can serve as signaling organelles by releasing low levels of reactive oxygen species (ROS) and TCA cycle metabolites that are essential for hypoxic activation of HIF, antigen activation of T cells, cellular differentiation and proliferation of cancer cells. The anti-diabetic drug metformin has been proposed to inhibit mitochondrial complex I. We will present data indicating that metformin inhibits mitochondrial complex I to exert it’s biological effects through controlling ROS, ATP, and NAD+.

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