Differential roles of Sall4 isoforms in embryonic stem cell pluripotency
Open accessAbstract
Murine embryonic stem (ES) cells are defined by continuous self-renewal and pluripotency. A diverse repertoire of protein isoforms arising from alternative splicing is expressed in ES cells without defined biological roles. Sall4, a transcription factor essential for pluripotency, exists as two isoforms (Sall4a and Sall4b). Both isoforms can form homodimers and a heterodimer with each other, and each can interact with Nanog. By genomewide location analysis, we determined that Sall4a and Sall4b have overlapping, but not identical binding sites within the ES cell genome. In addition, Sall4b, but not Sall4a, binds preferentially to highly expressed loci in ES cells. Sall4a and Sall4b binding sites are distinguished by both epigenetic marks at target loci and their clustering with binding sites of other pluripotency factors. When ES cells expressing a single isoform of Sall4 are generated, Sall4b alone could maintain the pluripotent state, although it could not completely suppress all differentiation markers. Sall4a and Sall4b collaborate in maintenance of the pluripotent state but play distinct roles. Our work is novel in establishing such isoform-specific differences in ES cells.
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As cells enter differentiation, expression of SALL4 drops.
“as cells enter differentiation, expression of SALL4 drops (Rao et al., 2010)”
From SALL4 controls cell fate in response to DNA base composition (2021) · cites this paper as Rao et al., 2010
Previous studies of Sall4 function in ESCs have produced conflicting conclusions about the role of Sall4 in ESC self-renewal.
“Previous studies of Sall4 function in ESCs have produced conflicting conclusions about the role of Sall4 in ESC self-renewal (Rao et al., 2010; Sakaki-Yumoto et al., 2006; Tsubooka et al., 2009; Yuri et al., 2009; Zhang et al., 2006).”
From Sall4 controls differentiation of pluripotent cells independently of the Nucleosome Remodelling and Deacetylation (NuRD) complex (2016) · cites this paper as Rao et al., 2010
Previous studies of Sall4 binding to the ESC genome used mouse microarrays (ChIP-Chip) with coverage biased towards genes and promoters, and therefore do not provide genome-wide coverage.
“Previous studies of Sall4 binding to the ESC genome used mouse microarrays (ChIP-Chip), the coverage of which is heavily biased towards genes and promoters, and therefore do not provide genome-wide coverage”
From Sall4 controls differentiation of pluripotent cells independently of the Nucleosome Remodelling and Deacetylation (NuRD) complex (2016) · cites this paper as Rao et al., 2010
In ESCs, SALL4B is sufficient to maintain ESC identity in the absence of SALL4A.
“In ESCs, SALL4B is sufficient to maintain ESC identity in the absence of SALL4A (Rao et al, 2010).”
From Structure of SALL4 zinc finger domain reveals link between AT-rich DNA binding and Okihiro syndrome (2023) · cites this paper as Rao et al, 2010
SALL1 protein is expressed in ESCs, is targeted to heterochromatin, and forms homo- and heterodimers with SALL4.
“Like SALL4, SALL1 protein is expressed in ESCs, is targeted to heterochromatin, and forms homo- and heterodimers with SALL4 (Yamashita et al, 2007; Rao et al, 2010).”
From Structure of SALL4 zinc finger domain reveals link between AT-rich DNA binding and Okihiro syndrome (2023) · cites this paper as Rao et al, 2010
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References 49 · Cited by 173
- Authors
- Rao, S., Zhen, S., Roumiantsev, S., McDonald, L. T., Yuan, G.-C., & Orkin, S. H.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Massachusetts General Hospital (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Orkin, Stuart H.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2010-11-01
- Volume
- 30
- Issue
- 22
- Pages
- 5364-5380
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2976381
- OpenAlex
- W2114951390
- Cited by
- 173
- References
- 49
- Citations by year
- 2025: 9 · 2024: 5 · 2023: 12 · 2022: 9 · 2021: 13 · 2020: 12 · 2019: 7 · 2018: 8 · 2017: 13 · 2016: 17 · 2015: 15 · 2014: 13 · 2013: 12 · 2012: 18
- FWCI
- 5.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (5K08HL87951, K08HL087951)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- SALL4, protein isoforms, alternative splicing, embryonic stem cells, pluripotency, Nanog, transcription factor binding sites, epigenetic modifications, self-renewal, differentiation, isoform-specific function
- MeSH terms
- Nanog Homeobox Protein, Amino Acid Sequence, Animals, Base Sequence, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, Humans, Molecular Sequence Data, Transcription Factors, Homeodomain Proteins, Gene Expression Regulation, Developmental, Dimerization, Protein Isoforms, Protein Structure, Quaternary, Pluripotent Stem Cells, Epigenesis, Genetic, Microarray Analysis, Mice
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