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Article ; Online: Maintaining Transcriptional Specificity Through Mitosis.

Ito, Kenji / Zaret, Kenneth S

Annual review of genomics and human genetics

2022 Volume 23, Page(s) 53–71

Abstract: Virtually all cell types have the same DNA, yet each type exhibits its own cell-specific pattern of gene expression. During the brief period of mitosis, the chromosomes exhibit changes in protein composition and modifications, a marked condensation, and ... ...

Abstract	Virtually all cell types have the same DNA, yet each type exhibits its own cell-specific pattern of gene expression. During the brief period of mitosis, the chromosomes exhibit changes in protein composition and modifications, a marked condensation, and a consequent reduction in transcription. Yet as cells exit mitosis, they reactivate their cell-specific programs with high fidelity. Initially, the field focused on the subset of transcription factors that are selectively retained in, and hence bookmark, chromatin in mitosis. However, recent studies show that many transcription factors can be retained in mitotic chromatin and that, surprisingly, such retention can be due to nonspecific chromatin binding. Here, we review the latest studies focusing on low-level transcription via promoters, rather than enhancers, as contributing to mitotic memory, as well as new insights into chromosome structure dynamics, histone modifications, cell cycle signaling, and nuclear envelope proteins that together ensure the fidelity of gene expression through a round of mitosis.
MeSH term(s)	Chromatin/genetics ; Chromosomes/genetics ; Histone Code ; Humans ; Mitosis/genetics ; Transcription Factors/genetics
Chemical Substances	Chromatin ; Transcription Factors
Language	English
Publishing date	2022-04-19
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2037670-4
ISSN	1545-293X ; 1527-8204
ISSN (online)	1545-293X
ISSN	1527-8204
DOI	10.1146/annurev-genom-121321-094603
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Article ; Online: Cellular reprogramming in vivo initiated by SOX4 pioneer factor activity.

Katsuda, Takeshi / Sussman, Jonathan H / Ito, Kenji / Katznelson, Andrew / Yuan, Salina / Takenaka, Naomi / Li, Jinyang / Merrell, Allyson J / Cure, Hector / Li, Qinglan / Rasool, Reyaz Ur / Asangani, Irfan A / Zaret, Kenneth S / Stanger, Ben Z

Nature communications

2024 Volume 15, Issue 1, Page(s) 1761

Abstract: Tissue damage elicits cell fate switching through a process called metaplasia, but how the starting cell fate is silenced and the new cell fate is activated has not been investigated in animals. In cell culture, pioneer transcription factors mediate " ... ...

Abstract	Tissue damage elicits cell fate switching through a process called metaplasia, but how the starting cell fate is silenced and the new cell fate is activated has not been investigated in animals. In cell culture, pioneer transcription factors mediate "reprogramming" by opening new chromatin sites for expression that can attract transcription factors from the starting cell's enhancers. Here we report that SOX4 is sufficient to initiate hepatobiliary metaplasia in the adult mouse liver, closely mimicking metaplasia initiated by toxic damage to the liver. In lineage-traced cells, we assessed the timing of SOX4-mediated opening of enhancer chromatin versus enhancer decommissioning. Initially, SOX4 directly binds to and closes hepatocyte regulatory sequences via an overlapping motif with HNF4A, a hepatocyte master regulatory transcription factor. Subsequently, SOX4 exerts pioneer factor activity to open biliary regulatory sequences. The results delineate a hierarchy by which gene networks become reprogrammed under physiological conditions, providing deeper insight into the basis for cell fate transitions in animals.
MeSH term(s)	Animals ; Mice ; Cell Differentiation/genetics ; Cellular Reprogramming/genetics ; Chromatin ; Metaplasia ; Transcription Factors/metabolism
Chemical Substances	Chromatin ; Transcription Factors ; Sox4 protein, mouse
Language	English
Publishing date	2024-02-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45939-z
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Article: Physiological reprogramming

Katsuda, Takeshi / Sussman, Jonathan / Ito, Kenji / Katznelson, Andrew / Yuan, Salina / Li, Jinyang / Merrell, Allyson J / Takenaka, Naomi / Cure, Hector / Li, Qinglan / Rasool, Reyaz Ur / Asangani, Irfan A / Zaret, Kenneth S / Stanger, Ben Z

bioRxiv : the preprint server for biology

2023

Abstract	Tissue damage elicits cell fate switching through a process called metaplasia, but how the starting cell fate is silenced and the new cell fate is activated has not been investigated in animals. In cell culture, pioneer transcription factors mediate "reprogramming" by opening new chromatin sites for expression that can attract transcription factors from the starting cell's enhancers. Here we report that Sox4 is sufficient to initiate hepatobiliary metaplasia in the adult liver. In lineage-traced cells, we assessed the timing of Sox4-mediated opening of enhancer chromatin versus enhancer decommissioning. Initially, Sox4 directly binds to and closes hepatocyte regulatory sequences via a motif it overlaps with Hnf4a, a hepatocyte master regulator. Subsequently, Sox4 exerts pioneer factor activity to open biliary regulatory sequences. The results delineate a hierarchy by which gene networks become reprogrammed under physiological conditions, providing deeper insight into the basis for cell fate transitions in animals.
Language	English
Publishing date	2023-02-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.02.14.528556
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Article ; Online: Mentorship in Science: Response to AlShebli et al., Nature Communications 2020.

Mummery, Christine / Little, Melissa / Lin, Haifan / Clark, Amander / Zaret, Ken / Srivastava, Deepak / Fuchs, Elaine / Watt, Fiona / Temple, Sally

Stem cell reports

2021 Volume 16, Issue 1, Page(s) 1–2

Language	English
Publishing date	2021-01-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2720528-9
ISSN	2213-6711 ; 2213-6711
ISSN (online)	2213-6711
ISSN	2213-6711
DOI	10.1016/j.stemcr.2020.12.016
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Article ; Online: Understanding impediments to cellular conversion to pluripotency by assessing the earliest events in ectopic transcription factor binding to the genome.

Soufi, Abdenour / Zaret, Kenneth S

Cell cycle (Georgetown, Tex.)

2013 Volume 12, Issue 10, Page(s) 1487–1491

Abstract: ... that reported in ES and iPS cells, distal enhancer sites in closed chromatin dominate the initial O, S, K and M ... binding distribution, showing that promoter occupancy is a later event in reprogramming. O, S and K act ... as pioneer factors for c-Myc, and c-Myc enhances the engagement of O, S and K. Despite the ability of OSKM ...

Abstract	In all known cases of transcription factor (TF)-based reprogramming, the process is relatively slow and inefficient. For example, it takes about a month for the ectopic expression of the transcription factors Oct4, Sox2, Klf4 and c-Myc (OSKM) to fully reprogram human somatic cells to pluripotency. Furthermore, recent studies indicate that there is an initial stochastic phase, whereby random cells in the converting population begin to express a few genes of the new fate, followed by a so-called deterministic phase, whereby activation of a network for the new fate leads to homogeneous changes in gene expression patterns within a subset of the cell population. We recently mapped the initial interactions between OSKM factors and the human genome during the first 48 h of human fibroblast conversion to pluripotency. Unlike that reported in ES and iPS cells, distal enhancer sites in closed chromatin dominate the initial O, S, K and M binding distribution, showing that promoter occupancy is a later event in reprogramming. O, S and K act as pioneer factors for c-Myc, and c-Myc enhances the engagement of O, S and K. Despite the ability of OSKM to access closed chromatin, megabase-scale chromatin regions in somatic cells, referred to as "differentially bound regions" (DBRs), are remarkably refractory to OSKM binding at 48 h, though they become bound in pluripotent cells. These DBRs are highly enriched for the repressive H3K9me3 mark and span genes at the top of the deterministic hierarchy. Transient knockdown of the relevant chromatin modifiers allows access of OSKM to DBRs and a more rapid and efficient conversion to pluripotency. Thus, overcoming DBR barriers helps explain the conversion from a stochastic to a deterministic phase of transcription factor-mediated cell type conversion.
MeSH term(s)	Cell Lineage ; Cellular Reprogramming ; Embryonic Stem Cells/cytology ; Genome ; Heterochromatin/metabolism ; Humans ; Induced Pluripotent Stem Cells/cytology ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/metabolism ; Octamer Transcription Factor-3/genetics ; Octamer Transcription Factor-3/metabolism ; Protein Binding ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; SOXB1 Transcription Factors/genetics ; SOXB1 Transcription Factors/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	GKLF protein ; Heterochromatin ; Kruppel-Like Transcription Factors ; Octamer Transcription Factor-3 ; Proto-Oncogene Proteins c-myc ; SOXB1 Transcription Factors ; Transcription Factors
Language	English
Publishing date	2013-04-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.24663
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Article ; Online: Carm1-arginine methylation of the transcription factor C/EBPα regulates transdifferentiation velocity.

Torcal Garcia, Guillem / Kowenz-Leutz, Elisabeth / Tian, Tian V / Klonizakis, Antonis / Lerner, Jonathan / De Andres-Aguayo, Luisa / Sapozhnikova, Valeriia / Berenguer, Clara / Carmona, Marcos Plana / Casadesus, Maria Vila / Bulteau, Romain / Francesconi, Mirko / Peiro, Sandra / Mertins, Philipp / Zaret, Kenneth / Leutz, Achim / Graf, Thomas

eLife

2023 Volume 12

Abstract: Here, we describe how the speed of C/EBPα-induced B cell to macrophage transdifferentiation (BMT) can be regulated, using both mouse and human models. The identification of a mutant of C/EBPα (C/ ... ...

Abstract	Here, we describe how the speed of C/EBPα-induced B cell to macrophage transdifferentiation (BMT) can be regulated, using both mouse and human models. The identification of a mutant of C/EBPα (C/EBPα
MeSH term(s)	Animals ; Humans ; Mice ; CCAAT-Enhancer-Binding Protein-alpha/genetics ; CCAAT-Enhancer-Binding Protein-alpha/metabolism ; Cell Differentiation/genetics ; Cell Transdifferentiation ; Chromatin ; Methylation ; Proto-Oncogene Proteins/metabolism ; Trans-Activators/genetics ; Trans-Activators/metabolism
Chemical Substances	CCAAT-Enhancer-Binding Protein-alpha ; Chromatin ; Proto-Oncogene Proteins ; Trans-Activators ; coactivator-associated arginine methyltransferase 1 (EC 2.1.1.319) ; CEBPA protein, human
Language	English
Publishing date	2023-06-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.83951
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Article ; Online: A LAMP sequencing approach for high-throughput co-detection of SARS-CoV-2 and influenza virus in human saliva.

Warneford-Thomson, Robert / Shah, Parisha P / Lundgren, Patrick / Lerner, Jonathan / Morgan, Jason / Davila, Antonio / Abella, Benjamin S / Zaret, Kenneth / Schug, Jonathan / Jain, Rajan / Thaiss, Christoph A / Bonasio, Roberto

eLife

2022 Volume 11

Abstract: The COVID-19 pandemic has created an urgent need for rapid, effective, and low-cost SARS-CoV-2 diagnostic testing. Here, we describe COV-ID, an approach that combines RT-LAMP with deep sequencing to detect SARS-CoV-2 in unprocessed human saliva with a ... ...

Abstract	The COVID-19 pandemic has created an urgent need for rapid, effective, and low-cost SARS-CoV-2 diagnostic testing. Here, we describe COV-ID, an approach that combines RT-LAMP with deep sequencing to detect SARS-CoV-2 in unprocessed human saliva with a low limit of detection (5-10 virions). Based on a multi-dimensional barcoding strategy, COV-ID can be used to test thousands of samples overnight in a single sequencing run with limited labor and laboratory equipment. The sequencing-based readout allows COV-ID to detect multiple amplicons simultaneously, including key controls such as host transcripts and artificial spike-ins, as well as multiple pathogens. Here, we demonstrate this flexibility by simultaneous detection of 4 amplicons in contrived saliva samples: SARS-CoV-2, influenza A, human
MeSH term(s)	COVID-19/diagnosis ; Humans ; Orthomyxoviridae ; Pandemics ; RNA, Viral/analysis ; SARS-CoV-2/genetics ; Saliva ; Sensitivity and Specificity
Chemical Substances	RNA, Viral
Language	English
Publishing date	2022-05-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.69949
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Article: Hepatocyte differentiation: from the endoderm and beyond.

Zaret, K S

Current opinion in genetics & development

2001 Volume 11, Issue 5, Page(s) 568–574

Abstract: Hepatocytes differentiate from the endoderm during embryonic development. Recent studies show, however, that hepatocytes can also be derived from rare cells that reside in the pancreas, bone marrow, and brain. Indeed, the latest discoveries indicate that ...

Abstract	Hepatocytes differentiate from the endoderm during embryonic development. Recent studies show, however, that hepatocytes can also be derived from rare cells that reside in the pancreas, bone marrow, and brain. Indeed, the latest discoveries indicate that embryonic hepatocytes normally arise by diversion of an endodermal cell population that would otherwise default to a pancreatic fate. Convergent FGF and BMP signals from distinct mesodermal cell types control this transition. Molecular signals that govern the differentiation of hepatocytes from non-endodermal cells and the role of such cells in normal liver physiology remain to be discovered.
MeSH term(s)	Animals ; Cell Differentiation ; Cell Lineage ; Endoderm/cytology ; Endoderm/metabolism ; Hematopoietic Stem Cells/cytology ; Hepatocytes/cytology ; Hepatocytes/metabolism ; Humans ; Liver/cytology ; Liver/embryology ; Mesoderm/cytology ; Mesoderm/metabolism ; Neurons/cytology ; Pancreas/cytology ; Signal Transduction ; Stem Cells/cytology
Language	English
Publishing date	2001-10
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	1077312-5
ISSN	1879-0380 ; 0959-437X
ISSN (online)	1879-0380
ISSN	0959-437X
DOI	10.1016/s0959-437x(00)00234-3
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Zs.A 3240: Show issues

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Article: Liver specification and early morphogenesis.

Zaret, K S

Mechanisms of development

2000 Volume 92, Issue 1, Page(s) 83–88

Abstract: The classically defined induction of the liver from the endoderm, elicited by the cardiac mesoderm, has recently been discovered to involve signaling by fibroblast growth factors (FGFs). Multiple FGFs induce hepatic gene expression independent of an ... ...

Abstract	The classically defined induction of the liver from the endoderm, elicited by the cardiac mesoderm, has recently been discovered to involve signaling by fibroblast growth factors (FGFs). Multiple FGFs induce hepatic gene expression independent of an effect on growth. A subset of these FGFs cooperates with other factors to promote morphogenesis of the newly specified hepatocytes. Subsequent to the formation of the liver bud, distinct mesenchymal signals and hepatic response pathways stimulate further growth and differentiation of the hepatic parenchymal cells and prevent apoptosis. The initial stages of hepatogenesis are therefore beginning to be understood, and serve as a paradigm for the development of other tissues from the endoderm.
MeSH term(s)	Animals ; Apoptosis ; Endoderm ; Fibroblast Growth Factors/physiology ; Liver/embryology ; Mice ; Mice, Knockout ; Models, Biological ; Morphogenesis ; Neovascularization, Physiologic ; Pancreas/embryology ; Signal Transduction
Chemical Substances	Fibroblast Growth Factors (62031-54-3)
Language	English
Publishing date	2000-03-15
Publishing country	Ireland
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	1055986-3
ISSN	1872-6356 ; 0925-4773
ISSN (online)	1872-6356
ISSN	0925-4773
DOI	10.1016/s0925-4773(99)00326-3
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Article: In vivo analysis of chromatin structure.

Zaret, K S

Methods in enzymology

1999 Volume 304, Page(s) 612–626

MeSH term(s)	Animals ; Cell Membrane Permeability ; Cell Nucleus/ultrastructure ; Chromatin/genetics ; Chromatin/ultrastructure ; Cross-Linking Reagents ; DNA/chemistry ; DNA/isolation & purification ; Deoxyribonuclease I ; Indicators and Reagents ; Nucleosomes/genetics ; Nucleosomes/ultrastructure ; Polymerase Chain Reaction/methods ; Potassium Permanganate ; Restriction Mapping/methods ; Sulfuric Acid Esters ; Ultraviolet Rays
Chemical Substances	Chromatin ; Cross-Linking Reagents ; Indicators and Reagents ; Nucleosomes ; Sulfuric Acid Esters ; Potassium Permanganate (00OT1QX5U4) ; DNA (9007-49-2) ; Deoxyribonuclease I (EC 3.1.21.1) ; dimethyl sulfate (JW5CW40Z50)
Language	English
Publishing date	1999
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ISSN	0076-6879
ISSN	0076-6879
DOI	10.1016/s0076-6879(99)04036-7
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