scholarly journals Balancing dynamic tradeoffs drives cellular reprogramming

2018 ◽  
Author(s):  
Kimberley N. Babos ◽  
Kate E. Galloway ◽  
Kassandra Kisler ◽  
Madison Zitting ◽  
Yichen Li ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Division ◽  
Motor Neuron ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cellular Reprogramming ◽  
Cellular Event ◽  
Chemical Factors ◽  
Number Of Cells ◽  
Transcription And Replication

AbstractAlthough cellular reprogramming continues to generate new cell types, reprogramming remains a rare cellular event. The molecular mechanisms that limit reprogramming, particularly to somatic lineages, remain unclear. By examining fibroblast-to-motor neuron conversion, we identify a previously unappreciated dynamic between transcription and replication that determines reprogramming competency. Transcription factor overexpression forces most cells into states that are refractory to reprogramming and are characterized by either hypertranscription with little cell division, or hyperproliferation with low transcription. We identify genetic and chemical factors that dramatically increase the number of cells capable of both hypertranscription and hyperproliferation. Hypertranscribing, hyperproliferating cells reprogram at 100-fold higher, near-deterministic rates. We demonstrate that elevated topoisomerase expression endows cells with privileged reprogramming capacity, suggesting that biophysical constraints limit cellular reprogramming to rare events.

Cell Reprogramming: The Many Roads to Success

2019 ◽  
Vol 35 (1) ◽  
pp. 433-452 ◽  
Author(s):  
Begüm Aydin ◽  
Esteban O. Mazzoni
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cellular Reprogramming ◽  
Cell Reprogramming ◽  
Direct Reprogramming ◽  
Cell Fate Conversion ◽  
The Many ◽  
Shed Light

Cellular reprogramming experiments from somatic cell types have demonstrated the plasticity of terminally differentiated cell states. Recent efforts in understanding the mechanisms of cellular reprogramming have begun to elucidate the differentiation trajectories along the reprogramming processes. In this review, we focus mainly on direct reprogramming strategies by transcription factors and highlight the variables that contribute to cell fate conversion outcomes. We review key studies that shed light on the cellular and molecular mechanisms by investigating differentiation trajectories and alternative cell states as well as transcription factor regulatory activities during cell fate reprogramming. Finally, we highlight a few concepts that we believe require attention, particularly when measuring the success of cell reprogramming experiments.

scholarly journals Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division

2018 ◽  
Author(s):  
Evgeny Zatulovskiy ◽  
Daniel F. Berenson ◽  
Benjamin R. Topacio ◽  
Jan M. Skotheim
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Growth ◽  
Cell Size ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Inverse Correlation ◽  
Cell Types ◽  
Similar Amount ◽  
Cell Cycle Inhibitor

Cell size is fundamental to function in different cell types across the human body because it sets the scale of organelle structures, biosynthesis, and surface transport1,2. Tiny erythrocytes squeeze through capillaries to transport oxygen, while the million-fold larger oocyte divides without growth to form the ~100 cell pre-implantation embryo. Despite the vast size range across cell types, cells of a given type are typically uniform in size likely because cells are able to accurately couple cell growth to division3–6. While some genes whose disruption in mammalian cells affects cell size have been identified, the molecular mechanisms through which cell growth drives cell division have remained elusive7–12. Here, we show that cell growth acts to dilute the cell cycle inhibitor Rb to drive cell cycle progression from G1 to S phase in human cells. In contrast, other G1/S regulators remained at nearly constant concentration. Rb is a stable protein that is synthesized during S and G2 phases in an amount that is independent of cell size. Equal partitioning to daughter cells of chromatin bound Rb then ensures that all cells at birth inherit a similar amount of Rb protein. RB overexpression increased cell size in tissue culture and a mouse cancer model, while RB deletion decreased cell size and removed the inverse correlation between cell size at birth and the duration of G1 phase. Thus, Rb-dilution by cell growth in G1 provides a long-sought cell autonomous molecular mechanism for cell size homeostasis.

scholarly journals An Algorithm for Cellular Reprogramming

2017 ◽  
Author(s):  
Scott Ronquist ◽  
Geoff Patterson ◽  
Markus Brown ◽  
Stephen Lindsly ◽  
Haiming Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Cell Biology ◽  
Human Fibroblasts ◽  
Cell Types ◽  
Approximate Model ◽  
Cellular Reprogramming ◽  
Biological Processes ◽  
Moderate Complexity

AbstractThe day we understand the time evolution of subcellular elements at a level of detail comparable to physical systems governed by Newton’s laws of motion seems far away. Even so, quantitative approaches to cellular dynamics add to our understanding of cell biology, providing data-guided frameworks that allow us to develop better predictions about, and methods for, control over specific biological processes and system-wide cell behavior. In this paper, we describe an approach to optimizing the use of transcription factors (TFs) in the context of cellular reprogramming. We construct an approximate model for the natural evolution of a cell cycle synchronized population of human fibroblasts, based on data obtained by sampling the expression of 22,083 genes at several time points along the cell cycle. In order to arrive at a model of moderate complexity, we cluster gene expression based on the division of the genome into topologically associating domains (TADs) and then model the dynamics of the TAD expression levels. Based on this dynamical model and known bioinformatics, such as transcription factor binding sites (TFBS) and functions, we develop a methodology for identifying the top transcription factor candidates for a specific cellular reprogramming task. The approach used is based on a device commonly used in optimal control. Our data-guided methodology identifies a number of transcription factors previously validated for reprogramming and/or natural differentiation. Our findings highlight the immense potential of dynamical models, mathematics, and data-guided methodologies for improving strategies for control over biological processes.Significance StatementReprogramming the human genome toward any desirable state is within reach; application of select transcription factors drives cell types toward different lineages in many settings. We introduce the concept of data-guided control in building a universal algorithm for directly reprogramming any human cell type into any other type. Our algorithm is based on time series genome transcription and architecture data and known regulatory activities of transcription factors, with natural dimension reduction using genome architectural features. Our algorithm predicts known reprogramming factors, top candidates for new settings, and ideal timing for application of transcription factors. This framework can be used to develop strategies for tissue regeneration, cancer cell reprogramming, and control of dynamical systems beyond cell biology.

Development of several epidermal cell types can be specified by the same MYB-related plant transcription factor

Development ◽  
1998 ◽  
Vol 125 (17) ◽  
pp. 3497-3508 ◽  
Author(s):  
B.J. Glover ◽  
M. Perez-Rodriguez ◽  
C. Martin
Keyword(s):  
Transcription Factor ◽  
Cell Division ◽  
Cell Types ◽  
The Novel ◽  
Transgenic Tobacco Plants ◽  
Developmental Pathway ◽  
Tobacco Plants ◽  
Cell Form ◽  
Related Transcription Factor ◽  
Related Plant

A MYB-related transcription factor (MIXTA) that controls development of conical cell form is expressed only in the inner epidermis of Antirrhinum petals. Expression of this gene throughout transgenic tobacco plants leads to excess numbers of multicellular trichomes on leaves and floral organs as well as the novel production of conical cells on leaves. These data indicate that conical cells and trichomes are produced by a common developmental pathway. The timing of MIXTA expression suggests that the choice between the cell types depends on the competence for cell division at the time at which the controlling gene is expressed. Duplication of genes and their association with different cis-regulatory regions may therefore result in the specification of novel plant cell types.

scholarly journals Expression profiling reveals novel role of Hunchback in retinal glia cell development and blood-brain barrier integrity

2017 ◽  
Author(s):  
Montserrat Torres-Oliva ◽  
Julia Schneider ◽  
Gordon Wiegleb ◽  
Felix Kaufholz ◽  
Nico Posnien
Keyword(s):  
Transcription Factor ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cell Development ◽  
Brain Barrier ◽  
Gene Clustering ◽  
Glia Cell ◽  
Blood Brain

AbstractThe development of different cell types must be tightly coordinated in different organs. The developing head of Drosophila melanogaster represents an excellent model to study the molecular mechanisms underlying this coordination because the eye-antennal imaginal discs contain the organ anlagen of nearly all adult head structures, such as the compound eyes or the antennae. We studied the genome wide gene expression dynamics during eye-antennal disc development in D. melanogaster to identify new central regulators of the underlying gene regulatory network. Expression based gene clustering and transcription factor motif enrichment analyses revealed a central regulatory role of the transcription factor Hunchback (Hb). We confirmed that hb is expressed in two polyploid retinal subperineurial glia cells (carpet cells). Our functional analysis shows that Hb is necessary for carpet cell development and loss of Hb function results in abnormal glia cell migration and photoreceptor axon guidance patterns. Additionally, we show for the first time that the carpet cells are an integral part of the blood-brain barrier.

The basic-helix-loop-helix protein pod1 is critically important for kidney and lung organogenesis

Development ◽  
1999 ◽  
Vol 126 (24) ◽  
pp. 5771-5783 ◽  
Author(s):  
S.E. Quaggin ◽  
L. Schwartz ◽  
S. Cui ◽  
P. Igarashi ◽  
J. Deimling ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Perinatal Period ◽  
Branching Morphogenesis ◽  
Bhlh Transcription Factor ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Kidney Morphogenesis

Epithelial-mesenchymal interactions are required for the development of all solid organs but few molecular mechanisms that underlie these interactions have been identified. Pod1 is a basic-helix-loop-helix (bHLH) transcription factor that is highly expressed in the mesenchyme of developing organs that include the lung, kidney, gut and heart and in glomerular visceral epithelial cells (podocytes). To determine the function of Pod1 in vivo, we have generated a lacZ-expressing null Pod1 allele. Null mutant mice are born but die in the perinatal period with severely hypoplastic lungs and kidneys that lack alveoli and mature glomeruli. Although Pod1 is exclusively expressed in the mesenchyme and podocytes, major defects are observed in the adjacent epithelia and include abnormalities in epithelial differentiation and branching morphogenesis. Pod1 therefore appears to be essential for regulating properties of the mesenchyme that are critically important for lung and kidney morphogenesis. Defects specific to later specialized cell types where Pod1 is expressed, such as the podocytes, were also observed, suggesting that this transcription factor may play multiple roles in kidney morphogenesis.

scholarly journals When fate follows age: unequal centrosomes in asymmetric cell division

2014 ◽  
Vol 369 (1650) ◽  
pp. 20130466 ◽  
Author(s):  
Jose Reina ◽  
Cayetano Gonzalez
Keyword(s):  
Stem Cells ◽  
Cell Division ◽  
Strong Correlation ◽  
Molecular Mechanisms ◽  
Asymmetric Cell Division ◽  
Current Knowledge ◽  
Cell Types ◽  
Functional Implications ◽  
Different Cell Types ◽  
Review Current

A strong correlation between centrosome age and fate has been reported in some stem cells and progenitors that divide asymmetrically. In some cases, such stereotyped centrosome behaviour is essential to endow stemness to only one of the two daughters, whereas in other cases causality is still uncertain. Here, we present the different cell types in which correlated centrosome age and fate has been documented, review current knowledge on the underlying molecular mechanisms and discuss possible functional implications of this process.

scholarly journals The Transcriptional Complex Sp1/KMT2A by Up-Regulating Restrictive Element 1 Silencing Transcription Factor Accelerates Methylmercury-Induced Cell Death in Motor Neuron-Like NSC34 Cells Overexpressing SOD1-G93A

2021 ◽  
Vol 15 ◽  
Author(s):  
Natascia Guida ◽  
Luca Sanguigno ◽  
Luigi Mascolo ◽  
Lucrezia Calabrese ◽  
Angelo Serani ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Motor Neuron ◽  
Molecular Mechanisms ◽  
Gene Promoter ◽  
Promoter Sequence ◽  
Protein Levels ◽  
Lysine Methyltransferase ◽  
Transcriptional Complex ◽  
Lateral Sclerosis

Methylmercury (MeHg) exposure has been related to amyotrophic lateral sclerosis (ALS) pathogenesis and molecular mechanisms of its neurotoxicity has been associated to an overexpression of the Restrictive Element 1 Silencing Transcription factor (REST). Herein, we evaluated the possibility that MeHg could accelerate neuronal death of the motor neuron-like NSC34 cells transiently overexpressing the human Cu2+/Zn2+superoxide dismutase 1 (SOD1) gene mutated at glycine 93 (SOD1-G93A). Indeed, SOD1-G93A cells exposed to 100 nM MeHg for 24 h showed a reduction in cell viability, as compared to cells transfected with empty vector or with unmutated SOD1 construct. Interestingly, cell survival reduction in SOD1-G93A cells was associated with an increase of REST mRNA and protein levels. Furthermore, MeHg increased the expression of the transcriptional factor Sp1 and promoted its binding to REST gene promoter sequence. Notably, Sp1 knockdown reverted MeHg-induced REST increase. Co-immunoprecipitation experiments demonstrated that Sp1 physically interacted with the epigenetic writer Lysine-Methyltransferase-2A (KMT2A). Moreover, knocking-down of KMT2A reduced MeHg-induced REST mRNA and protein increase in SOD1-G93A cells. Finally, we found that MeHg-induced REST up-regulation triggered necropoptotic cell death, monitored by RIPK1 increased protein expression. Interestingly, REST knockdown or treatment with the necroptosis inhibitor Necrostatin-1 (Nec) decelerated MeH-induced cell death in SOD1-G93A cells. Collectively, this study demonstrated that MeHg hastens necroptotic cell death in SOD1-G93A cells via Sp1/KMT2A complex, that by epigenetic mechanisms increases REST gene expression.

scholarly journals Pancreatic Ductal Morphogenesis and the Pdx1 Homeodomain Transcription Factor

2009 ◽  
Vol 20 (22) ◽  
pp. 4838-4844 ◽  
Author(s):  
Melanie P. Wescott ◽  
Meritxell Rovira ◽  
Maximilian Reichert ◽  
Johannes von Burstin ◽  
Anna Means ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Morphological Changes ◽  
3D Cell Culture ◽  
Cell Types ◽  
Branching Morphogenesis ◽  
Mouse Development ◽  
And Migration ◽  
Transcription Factor Expression ◽  
Pdx1 Expression

Embryonic development of the pancreas is marked by an early phase of dramatic morphogenesis, in which pluripotent progenitor cells of the developing pancreatic epithelium give rise to the full array of mature exocrine and endocrine cell types. The genetic determinants of acinar and islet cell lineages are somewhat well defined; however, the molecular mechanisms directing ductal formation and differentiation remain to be elucidated. The complex ductal architecture of the pancreas is established by a reiterative program of progenitor cell expansion and migration known as branching morphogenesis, or tubulogenesis, which proceeds in mouse development concomitantly with peak Pdx1 transcription factor expression. We therefore evaluated Pdx1 expression with respect to lineage-specific markers in embryonic sections of the pancreas spanning this critical period of duct formation and discovered an unexpected population of nonislet Pdx1-positive cells displaying physical traits of branching. We then established a 3D cell culture model of branching morphogenesis using primary pancreatic duct cells and identified a transient surge of Pdx1 expression exclusive to branching cells. From these observations we propose that Pdx1 might be involved temporally in a program of gene expression sufficient to facilitate the biochemical and morphological changes necessary for branching morphogenesis.

scholarly journals More than just Stem Cells: Functional Roles of the Transcription Factor Sox2 in Differentiated Glia and Neurons

2019 ◽  
Vol 20 (18) ◽  
pp. 4540 ◽  
Author(s):  
Sara Mercurio ◽  
Linda Serra ◽  
Silvia K. Nicolis
Keyword(s):  
Stem Cells ◽  
Nervous System ◽  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Movement Control ◽  
Cell Types ◽  
Animal Evolution ◽  
Sox2 Expression ◽  
Downstream Target

The Sox2 transcription factor, encoded by a gene conserved in animal evolution, has become widely known because of its functional relevance for stem cells. In the developing nervous system, Sox2 is active in neural stem cells, and important for their self-renewal; differentiation to neurons and glia normally involves Sox2 downregulation. Recent evidence, however, identified specific types of fully differentiated neurons and glia that retain high Sox2 expression, and critically require Sox2 function, as revealed by functional studies in mouse and in other animals. Sox2 was found to control fundamental aspects of the biology of these cells, such as the development of correct neuronal connectivity. Sox2 downstream target genes identified within these cell types provide molecular mechanisms for cell-type-specific Sox2 neuronal and glial functions. SOX2 mutations in humans lead to a spectrum of nervous system defects, involving vision, movement control, and cognition; the identification of neurons and glia requiring Sox2 function, and the investigation of Sox2 roles and molecular targets within them, represents a novel perspective for the understanding of the pathogenesis of these defects.

Sign in / Sign up

Export Citation Format

Share Document