Oct4 Targets Regulatory Nodes to Modulate Stem Cell Function

Abstract

Stem cells are characterized by two defining features, the ability to self-renew and to differentiate into highly specialized cell types. The POU homeodomain transcription factor Oct4 (Pou5f1) is an essential mediator of the embryonic stem cell state and has been implicated in lineage specific differentiation, adult stem cell identity, and cancer. Recent description of the regulatory networks which maintain ‘ES’ have highlighted a dual role for Oct4 in the transcriptional activation of genes required to maintain self-renewal and pluripotency while concomitantly repressing genes which facilitate lineage specific differentiation. However, the molecular mechanism by which Oct4 mediates differential activation or repression at these loci to either maintain stem cell identity or facilitate the emergence of alternate transcriptional programs required for the realization of lineage remains to be elucidated. To further investigate Oct4 function, we employed gene expression profiling together with a robust statistical analysis to identify genes highly correlated to Oct4. Gene Ontology analysis to categorize overrepresented genes has led to the identification of themes which may prove essential to stem cell identity, including chromatin structure, nuclear architecture, cell cycle control, DNA repair, and apoptosis. Our experiments have identified previously unappreciated roles for Oct4 for firstly, regulating chromatin structure in a state consistent with self-renewal and pluripotency, and secondly, facilitating the expression of genes that keeps the cell poised to respond to cues that lead to differentiation. Together, these data define the mechanism by which Oct4 orchestrates cellular regulatory pathways to enforce the stem cell state and provides important insight into stem cell function and cancer.

Ethanol Alters the Balance of Sox2, Oct4, and Nanog Expression in Distinct Subpopulations During Differentiation of Embryonic Stem Cells

“…Gene expression of Oct4 has been associated with several cell cycle and apoptosis genes in ES and differentiated cells [56]. Because our data demonstrated that Oct4 was modulated by ethanol (Figs.…”

“…As cells with low Nanog expression lose their pluripotency earlier than cells with higher Nanog levels [69], the expression pattern of Sox2, Oct4, and Nanog in S8 cells suggests that ethanol-exposed cells were differentiated beyond the Nanog gatekeeper barrier. Oct4 regulates several genes related to cell cycle and apoptosis, and downregulation of Oct4 during differentiation correlates positively with transcription of apoptotic genes and lineage commitment [56]. In our system, a twofold variation in the Oct4 protein level between differentiated cells exposed to ethanol and control cells did not translate into differences in the overall cell proliferation rate, cell cycle phase distribution, or apoptotic cells (Fig.…”

H3K9 histone acetylation predicts pluripotency and reprogramming capacity of ES cells

“…3 It was later shown that oocytes can also be employed for the cloning of mammals. 4,5 However, the efficiency of mammalian cloning, as measured by the production of live-birth clones, is low and it has been suggested that this is due to the incomplete reprogramming of the somatic nucleus. 6 Embryonic stem cells (ESCs), like oocytes, contain reprogramming activity, and can be employed to reprogram somatic genomes through fusion.…”

Neuronal Differentiation Capability of Nasal Polyps of Chronic Rhinosinusitis

“…Oct-4, a Pou domain-containing transcription factor, has become a proxy for stemness in many different studies of adult stem cells and is an essential mediator of the embryonic stem cell state (Campbell et al 2007;Lengner et al 2008). Oct-4 expression has been demonstrated at different locations in the human body like bone marrow, hair follicles, breast, liver, or neural stem cell (Gupta and Rosenberg 2008;Jiang et al 2002;Reyes et al 2002;Yu et al 2006) and now also in nasal polyp cells.…”