Bright/Arid3A Acts as a Barrier to Somatic Cell Reprogramming through Direct Regulation of Oct4, Sox2, and Nanog

Popowski, Melissa; Templeton, Troy D.; Lee, Bum Kyu; Rhee, Catherine; Li, He; Miner, Cathrine A.; Dekker, Joseph D.; Orlanski, Shari; Bergman, Yehudit; Iyer, Vishwanath R.; Webb, Carol F.; Tucker, Haley O.

doi:10.1016/j.stemcr.2013.12.002

Cited by 47 publications

(49 citation statements)

References 30 publications

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“…4D). These characteristics are all features specific to PV neurons (17). At 7-10 dpi, spontaneous action potentials were detected and could be abolished by TTX (Fig.…”

Section: Identification Of Forskolin As a Promising Candidate For Ipvmentioning

confidence: 72%

Conversion of Fibroblasts to Parvalbumin Neurons by One Transcription Factor, Ascl1, and the Chemical Compound Forskolin

Shi

Zhang

Chen

et al. 2016

Journal of Biological Chemistry

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Abnormalities in parvalbumin (PV)-expressing interneuronscause neurodevelopmental disorders such as epilepsy, autism, and schizophrenia. Unlike other types of neurons that can be efficiently differentiated from pluripotent stem cells, PV neurons were minimally generated using a conventional differentiation strategy. In this study we developed an adenovirus-based transdifferentiation strategy that incorporates an additional chemical compound for the efficient generation of induced PV (iPV) neurons. The chemical compound forskolin combined with Ascl1 induced ϳ80% of mouse fibroblasts to iPV neurons. The iPV neurons generated by this procedure matured 5-7 days post infection and were characterized by electrophysiological properties and known neuronal markers, such as PV and GABA. Our studies, therefore, identified an efficient approach for generating PV neurons.Parvalbumin interneurons are a small population of neurons that constitute the inhibitory modules of the cerebral cortex and hippocampus (1, 2). Although small in number and size, parvalbumin interneurons play important roles in a wide spectrum of brain functions, such as orchestrating the timing of various critical periods, synchronizing the electrical activities of certain brain cells, and rewiring the circuitry. The malfunction of these pivotal cells has been proven to be critical in autism, schizophrenia, and other neurodevelopmental disorders (1). PV 2 neurons originate primarily from the medial ganglionic eminence of the subcortical telencephalon. They mature slowly and spread throughout the brain over time. Until now the procurement and generation of specific type of neurons has depended on direct differentiation from pluripotent stem cells, such as embryonic stem cells or induced pluripotent stem cells. This common approach has been used for the generation of PV neurons (3). The generation of PV neurons for research and therapeutic purposes by other approaches needs to be investigated.Direct generation from one cell type to another provides a promising avenue for transplantable cells and holds great hope for cell-based therapy. Skin fibroblasts (mesodermal lineage) are an important source of starting cells that can be directly converted into a wide variety of cell types, including neurons (ectodermal lineage) (4, 5). Specific types of neurons, such as dopaminergic neurons (6 -8), spinal motor neurons (9), and cholinergic neurons (10) have also been efficiently converted from mouse or human fibroblasts. Thus, for late-born and slowly maturing neurons such as parvalbumin interneurons, it might be possible to surpass the laborious process of differentiation by obtaining functional cells through the direct conversion from other types of cells.Because of the side effect of integration associated with lentior retrovial delivery of exogenous genes, previous procedures used for transdifferentiation led to uncertainty in the genetic and epigenetic stability of the target cells. To explore suitable approaches for neuronal generation, we and other groups have d...

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“…4D). These characteristics are all features specific to PV neurons (17). At 7-10 dpi, spontaneous action potentials were detected and could be abolished by TTX (Fig.…”

Section: Identification Of Forskolin As a Promising Candidate For Ipvmentioning

confidence: 72%

Conversion of Fibroblasts to Parvalbumin Neurons by One Transcription Factor, Ascl1, and the Chemical Compound Forskolin

Shi

Zhang

Chen

et al. 2016

Journal of Biological Chemistry

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“…We previously showed that ARID3a enhances transcription of a subset of IgH promoters after B cell activation (11–14, 43, 44), and that it can act as a repressor of pluripotency genes, including Oct4, in somatic cells (45, 46). However, the gene targets and mechanisms by which ARID3a functions in HSPCs are unknown.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of the Transcription Factor ARID3a in Lupus Patient Hematopoietic Progenitor Cells

Ratliff

Ward

Merrill

et al. 2015

The Journal of Immunology

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Although hematopoietic progenitor/stem cells (HPSCs) are used for transplantation, characterization of the multiple subsets within this population in man has lagged behind similar studies in mice. We found that expression of the DNA-binding protein, ARID3a, in mouse stem cells was important for normal development of hematopoietic lineages; however, progenitors expressing ARID3a in man have not been defined. We previously showed increased numbers of ARID3a+ B cells in nearly half of systemic lupus erythematosus (SLE) patients, and that total numbers of ARID3a+ B cells were associated with increased disease severity. Because expression of ARID3a in those SLE patients occurred throughout all B cell subsets, we hypothesized that ARID3a expression in patient HSPCs might also be increased relative to expression in healthy controls. Our data now show that ARID3a expression is not limited to any defined subset of HPSCs in either healthy controls or SLE patients. Numbers of ARID3a+ HSPCs in SLE patients were increased over numbers of ARID3a+ cells in healthy controls. While all SLE-derived HPSCs exhibited poor colony formation in vitro compared to controls, SLE HPSCs with high numbers of ARID3a+ cells yielded increased numbers of cells expressing the early progenitor marker, CD34. SLE HPSCs with high numbers of ARID3a+ cells also more readily generated autoantibody producing cells than HPSCs with lower levels of ARID3a in a humanized mouse model. These data reveal new functions for ARID3a in early hematopoiesis and suggest that knowledge regarding ARID3a levels in HPSCs could be informative for applications requiring transplantation of those cells.

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“…Loss-of-function studies revealed that >98% of Arid3a À/À mice die prior to embryonic day 11.5 (E11.5) (Webb et al 2011), suggesting a potential role in embryonic development. A recent follow-up study showed that singular loss of Arid3a is sufficient for reprogramming as well as enhancement of standard four-factor reprogramming of mouse embryonic fibroblasts (MEFs) to fully induced pluripotent stem cells (Takahashi and Yamanaka 2006;Popowski et al 2014). That Arid3a is expressed highly in extraembryonic trophoblast lineages that give rise to the placenta (Wu et al 2009) led us to examine its function in ES cells and TE lineage commitment and differentiation.…”

Section: Cdx2mentioning

confidence: 99%

Arid3a is essential to execution of the first cell fate decision via direct embryonic and extraembryonic transcriptional regulation

et al. 2014

Self Cite

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Despite their origin from the inner cell mass, embryonic stem (ES) cells undergo differentiation to the trophectoderm (TE) lineage by repression of the ES cell master regulator Oct4 or activation of the TE master regulator Caudal-type homeobox 2 (Cdx2). In contrast to the in-depth studies of ES cell self-renewal and pluripotency, few TE-specific regulators have been identified, thereby limiting our understanding of mechanisms underlying the first cell fate decision. Here we show that up-regulation and nuclear entry of AT-rich interactive domain 3a (Arid3a) drives TE-like transcriptional programs in ES cells, maintains trophoblast stem (TS) cell selfrenewal, and promotes further trophoblastic differentiation both upstream and independent of Cdx2. Accordingly, Arid3a-/-mouse post-implantation placental development is severely impaired, resulting in early embryonic death. We provide evidence that Arid3a directly activates TE-specific and trophoblast lineage-specific genes while directly repressing pluripotency genes via differential regulation of epigenetic acetylation or deacetylation. Our results identify Arid3a as a critical regulator of TE and placental development through execution of the commitment and differentiation phases of the first cell fate decision.

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Bright/Arid3A Acts as a Barrier to Somatic Cell Reprogramming through Direct Regulation of Oct4, Sox2, and Nanog

Cited by 47 publications

References 30 publications

Conversion of Fibroblasts to Parvalbumin Neurons by One Transcription Factor, Ascl1, and the Chemical Compound Forskolin

Conversion of Fibroblasts to Parvalbumin Neurons by One Transcription Factor, Ascl1, and the Chemical Compound Forskolin

Differential Expression of the Transcription Factor ARID3a in Lupus Patient Hematopoietic Progenitor Cells

Arid3a is essential to execution of the first cell fate decision via direct embryonic and extraembryonic transcriptional regulation

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