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Role of Transcription Regulatory Complexes and Epigenetic Modifications in Driving the Cell Fate Decisions.

Byline: Syed A. Ali Verline Justilien Syed Z.H. Bukhari Jamieson Lee and Abdul R. Shakoori

Abstract Specific transcription factors and co-regulatory proteins cooperate to regulate the expression of phenotypic genes involved in driving the specific cell lineage. Epigenetic mechanisms such as histone and DNA CpG-methylation that are controlled by regulatory complexes also contribute in regulating cell fate decisions by regulating cellular transcription. During cancer a transformed cell faces cascade of external and internal signaling events that cause disruption of regulatory complexes and lead to failure of transcriptional machinery to run microenvironment. In general together perturbation of transcriptional and epigenetic events in a cancer cell results in abnormal regulation of cell proliferation growth and differentiation. These major biological mechanisms regulate tumor growth and progression during cancer. Recent findings have explored the existence of cancer stem-like" cells in the tumor that are resistant to chemo-therapy and radio-therapy.

These stem-like" cells can be identified in the tumor due to the expression of marker genes and epigenetic modifications. Many specific post-translational epigenetic modifications such as acetylation methylation and phosphorylation of the histones are linked to transcriptional regulation of cancer stem-like" phenotype. The current review briefly summarizes the importance of transcriptional regulatory complexes epigenetic markings and molecular events involved in stem-like" cell fate determination during cancer.

Key words: Transcription factors co-regulatory proteins epigenetic modifications cell fate regulation. EPIGENETIC REGULATORY COMPLEXES GENES TRANSCRIPTION AND CELL FATE

Cells demonstrate unique transcriptional and epigenetic (Histone and DNA) instructions in each specific lineage. These epigenetic modifications that regulate gene expression are reversible and controlled through transcriptional regulatory complexes (Boland et al. 2014; Goldberg et al. 2007; Hanna et al. 2008; Reik 2007). Histones post-translational modifications and gene promoters DNA CpG-methylation are the two well-studied epigenetic mechanisms that control gene transcription and influence the cell phenotype without altering the DNA sequence (Aithal and Rajeswari et al. 2013; Cedar and Bergman 2009; Miranda and Jones 2007; Ruthenburg et al. 2007; Shilatifard 2006). Association of epigenetic modifications and cellular phenotype are well addressed (Goldberg et al. 2007; Hanna et al. 2008; Reik 2007; Roy and Kundu 2014).

For example specific epigenetic modifications on the amino-terminal tails of histones are linked to gene activation and depression or heterochromatin formation that results in irreversible silencing (Ruthenburg et al. 2007; Shilatifard 2006). These epigenetic codes also reflect and provide information about the transcriptional regulatory complexes involved in dictating cell fate (Eguchi et al. 2014; Hanna et al. 2008; Cedar and Bergman 2009; Miranda and Jones 2007; Jenuwein and Allis 2001). In addition epigenetic gene bookmarking plays a key role in sustaining a transformed cell phenotype to assist tumor progression and more interestingly subsets of epigenetic modifications are inheritable to maintain cellular identity during lineage progression of transformed cells (Esteller 2008; Sarge and Park- Sarge 2005; Jones and Baylin 2007; Martin and Zhang 2007; Ng and Gurdon 2008; Probst et al. 2009).

Recent key observations demonstrate that some phenotypic transcription factors with co- regulatory proteins are retained on loci that are important for cell fate decisions (Rando and Verstrepen 2007; Ali et al. 2008; Xing et al. 2005

Young et al. 2007a) and constitutes a novel concept of architectural epigenetics" (Young et al. 2007b). Together regulatory factors and epigenetic modifications determine the fate of cell in specific lineage by regulating the expression of genes specific to cell phenotype we termed as fate specific or phenotypic genes". For extensive studies we refer to in-depth reviews elaborating multiple dimensions of epigenetic control (Goldberg et al. 2007; Jenuwein and Allis 2001; Zaidi et al. 2010 2014; Filipowicz et al. 2008; Goodrich and Kugel 2006).

Bookmarking of target genes regulates key cellular events of growth proliferation and cell differentiation (Moazed 2009; Groudine and Weiuntraub 1982; John and Workman 1998; Michelotti et al. 1997; Smith et al. 2002; Tang et al. 2003). For example in the mammals multiple repeat copies of the rRNA are tandemly organized in a head to tail fashion on acrocentric chromosomes and are transcribed by RNA polymerase I (Pol I). In interphase rRNA regulatory machinery is configured as round conspicuous body termed as nucleolus (Fig. 1) where ribosome biogenesis and the demand for protein synthesis are accommodated to regulate cell growth (Boisvert et al. 2007; Mayer and Grummt 2006; White 2005). During mitosis RNA Pol I transcription ceases and rRNA genes specifically reside at the short arm of the acrocentric chromosomes to form a structure called Nucleolar Organizer Regions (NORs Fig. 1) (Klein and Grummt 1999; Spence and Luthardt 1975).

However NORs carry interphase transcription regulatory machinery i.e. upstream binding factor (UBF) selectivity factor (SL1) and components of RNA Pol I factor that are key to facilitate rRNA gene transcription as cells come out of mitosis (Roussel et al. 1993). The retention of transcriptional regulatory proteins at the promoters of the phenotypic" genes through mitosis demonstrates a unique component of epigenetic control to support cell growth and proliferation following cell division. For more information on gene bookmarking by phenotypic factors and regulation of biological events readers are referred to classical research articles (Roussel et al. 1993; Lian et al. 2004; Ali et al. 2010; Berkes and Tapscot 2005; Kitzmann and Fernandez 2001; Mohun 1992).


Stem cells are defined by their ability to self- renew and generate population of cells that are different from the parent phenotype. Stem cells can divide by either asymmetric or symmetric modes of division and that the balance between these two modes is controlled by developmental and environmental signals to produce appropriate numbers of stem cells and differentiated daughters. Available data suggests that most stem cells have the ability to switch between asymmetric (ACD) and symmetric (SCD) modes of division depending on the cellular context and that the balance between these two modes of division is compromised during disease states that may cause stem cells to switch between symmetric and asymmetric cell divisions (Berika et al. 2014; Marjanovic et al. 2012).

For example both neural and epidermal progenitors change from primarily symmetric divisions that expand stem-cell pools during embryonic development to asymmetric divisions that expand differentiated cell numbers in mid to late gestation. For these cells divisions are classified as symmetric or asymmetric depending on whether one or both daughter cells retain the position and morphology associated with stem cells. As layers of differentiated cells arise in the forebrain progenitors increasingly undergo apparently asymmetric divisions: one cell remains in the ventricular zone (where stem cells are located) and the other cell migrates into overlying layers of differentiated neurons (Chenn and McConnell 1995; Noctor et al. 2004).

Consequently the concept of cancer stem cells has been emerging and focus is shifting towards cancer stem cell therapeutics (Le et al. 2014; Sherley et al. 2014). Cancer stem cells use symmetric divisions to self-renew and to generate differentiated progeny that are destined to acquire the same fate (Fig. 2 upper panel). A hallmark of all symmetric divisions is to increase the number of stem or differentiated cells. Symmetric stem-cell divisions are common during wound healing regeneration and have also been observed during the development of both vertebrates and invertebrates. The capacity for symmetric stem cell self-renewal may confer developmental plasticity increased growth and enhanced regenerative capacity; however it may also confer an inherent risk of cancer. Stem cells can rely either completely on symmetric divisions for tumor progression or on a combination of symmetric and asymmetric divisions.

Asymmetric cell division is unique aspect of stem cells in which a cell gives rise to two genetically identical cells but functionally different cells. One of the cells is destined for lineage progression while the other attains the characteristics of parent cell. Studies in yeast C. elegans and Drosophila have provided us a mechanistic process of asymmetric cell division (Armakolas et al. 2010; Cowan and Hyman 2004; Sousa-Nunes and Somers et al. 2013; Thorpe et al. 2008; Colman-Lerner et al. 2001) and furthermore in neurogenesis ACD also has been ascribed to cell fate decisions (Colman-Lerner et al. 2001; Januschke and Gonzalez 2008). One strategy by which cancer stem cells can accomplish these two tasks is asymmetric cell division whereby each stem cell divides to generate one daughter with a stem-cell fate (self-renewal) and one daughter that differentiate thus adding to the tumor heterogeneity (Chenn and McConnell 1995; Betschinger and Knoblich 2004;

Clevers 2005; Doe and Bowerman 2001; Yamashita et al. 2005; Lobo et al. 2007). Therefore asymmetric division is a particularly attractive strategy because it manages both tasks (tumor expansion and heterogeneity) with a single division (Fig. 2 upper panel). It is also possible that mammalian cells utilize ACD mechanisms to ensure the maintenance of cancer stem cells while giving rise to distinct lineages from common ancestor cell.

The role of asymmetric cell division in stem- cell and cancer stem cell coupled with the mechanisms that regulate this process have been extensively reviewed (Betschinger and Knoblich 2004; Clevers 2005; Doe and Bowerman 2001; Yamashita et al. 2005; Lobo et al. 2007; Gomez- Lopez et al. 2014). In brief two types of signaling cues govern cell fate decisions. The first relies on the asymmetric partitioning of cell components that determine cell fate; we refer to such mechanisms as intrinsic' (Fig. 2 lower panel). The second involves the asymmetric placement of daughter cells relative to external cues; we refer to these mechanisms as extrinsic' (Fig. 2 lower panel). Intrinsic mechanisms include regulated assembly of cell polarity factors and regulated segregation of cell fate determinants. In situations in which the only difference between the daughter cells is their position relative to the stem-cell niche

The daughter cells may initially have equivalent developmental potential but they may acquire different fates owing to exposure to varying external signals. In this way the division is asymmetric with respect to the ultimate fate of the daughter cells even though the division is intrinsically symmetric initially yielding two daughter cells with equivalent developmental potential. Recent findings suggest that the unequal distribution of non-genomic regulatory proteins is a defining factor for driving the specific lineage of a cell. Together recent findings highlight the fundamental role of symmetric and asymmetric distribution of transcription regulatory factors and epigenetic modifications in driving cell fate through target genes expression.


The ability of cancer initiating cells to switch back and forth between symmetric and asymmetric modes of division depending on developmental and environmental cues is a key adaptation that increases the capacity of tumor propagating cell to survive. A potential cost of the increased use of symmetric divisions by normal stem cells may be a higher incidence of cancer particularly the evidence that cancer frequently arises from the transformation of somatic stem cells. Moreover if tumor growth and progression are driven by cancer stem" cells then this process may remain biologically dependent on modes of division that permit the geometric expansion of stem cells. The idea that symmetric divisions are required for neoplastic proliferation remains hypothetical but raises the possibility that studies of the asymmetric division machinery could identify important new tumor suppressor mechanisms.

A key issue for the future is to explore how normal and cancer stem" cells are regulated to switch between asymmetric and symmetric divisions. A molecular understanding of this regulatory switch for cell division is not only relevant to basic stem-cell biology but also has tremendous clinical importance for controlling stem cells therapeutically.

In addition to that the mitotic association of regulatory proteins combined with the global genome-wide assessment of histone-DNA modifications provides an epigenetic profile of the signatures involved in cancer prognosis as well as monitoring chemo and radio based therapies. As a result of the extensive efforts to define transcriptional and epigenetic signatures patterns with both diagnostic and therapeutic value are emerging. Some of these will prove to be important for the cancer patients. The strategy of personalized medicine that is obtaining comprehensive genetic epigenetic and expression data from individuals patients and identifying the trends that correlate to disease onset and remission can be helpful for treatment based on patient's personal characteristics. It is important that physician and scientists combine their efforts to improve clinical trial by translating cancer bio-marker research.


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