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Retention and transmission of active transcription memory from progenitor to progeny cells via ligand-modulated transcription factors: elucidation of a concept by BIOPIT model
Sanjay Kumar, Mallampati Saradhi, Nagendra K. Chaturvedi and Rakesh K. Tyagi1
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India
Observations made in live cells have clearly demonstrated that agonist-activated steroid/nuclear receptors reorganize in the nucleoplasm into hundreds of discrete speckled structures commonly referred to as nuclear foci. Subsequent studies have shown that nuclear foci are formed only with agonist- and not with pure antagonist-bound receptors. Also, the other accessory components of transcriptional machinery co-localize in nuclear foci with the activated receptors, suggesting these to be active gene transcription sites. Recently, it has been observed that during mitosis nuclear foci present in interphase of progenitor cells co-migrate with condensing chromatin and are inherited into the progeny cells. Ensuing events imply that as memory, the cells inherit only a biomolecular blueprint of transcription status over to next generations to express and sustain their characteristic proteome. Thus, cells achieve self-renewal via mitosis but not without ensuring that the characteristic proteome and traits are distinctively preserved during this transcription phase. This mechanism, although somewhat analogous to epigenetic marking, differs in Nature since transcription factors themselves execute this transmission. To uphold the mechanistic distinctions the phenomenon has been termed BIOPIT (biomolecular imprints offered to progeny for inheritance of traits). The BIOPIT model proposed herein attempts to explain how the disruption of BIOPIT markings by therapeutic anti-hormones or endocrine disruptors over prolonged periods may lead to eradication of cellular transcription memory with deleterious cellular consequences. It is anticipated that our model has the potential to explain the concerted actions and consequences of ligand–receptor interactions with the chromatin in the perspective of normal and aberrant physiological situations.
Key words: mitotic chromatin, nuclear foci, nuclear receptor (NR), transcription memory
Abbreviations: AR, androgen receptor, BIOPIT, biomolecular imprints offered to progeny for inheritance of traits, CBP, CREB (cAMP-response-element-binding protein)-binding protein, ChIP, chromatin immunoprecipitation, DHT, dihydrotestosterone, FP, fluorescent protein, GFP, green fluorescent protein, GRIP1, glucocorticoid receptor-interacting protein 1, HMG, high mobility group, HSF2, heat shock transcription factor 2, NF-Y, nuclear factor Y, NR, nuclear receptor, PXR, pregnane X receptor, SRC-1, steroid receptor co-activator 1, TBP, TATA-box binding protein
1To whom correspondence should be addressed (email firstname.lastname@example.org or email@example.com).
A characteristic gene expression profile creates and sustains cellular traits and the types. In this context, the presence of a combination of transcription factors, with each one modulating hundreds of responsive genes, are crucial determinants in maintaining the cell-specific proteome. Among the transcription factors, the NR (nuclear receptor) superfamily is a large group of ligand-modulated transcription factors with 49 members presently identified. These transcription factors are implicated in numerous physiological processes, and have been prospective therapeutic targets for treatment of many critical diseases including hormone-related cancers (Evans, 1998; Escriva et al., 2004; Shank and Paschal, 2005; Kumar et al., 2006; McEwan, 2009). In view of the fact that ligand-induced movements and localization of transcription factors are one of the major phenomena for regulating the transcriptional activity, FP (fluorescent protein)-tagged NR chimaera have been consistently used for studying their dynamic behaviour in living cells (Shank and Paschal, 2005; Kumar et al., 2006; Griekspoor et al., 2007).
In principle, all intracellular NRs when bound to their cognate ligand are nuclear and transcriptionally active. Results obtained from FP-tagged receptors expressed and imaged in live cells have unvaryingly shown that agonist-bound receptors reorganize in the nucleoplasm into hundreds of discrete fluorescent speckles commonly referred to as nuclear foci (Stenoien et al., 2000; Tyagi et al., 2000; Baumann et al., 2001; Tomura et al., 2001; Karvonen et al., 2002; Saitoh et al., 2002; Black et al., 2004; Black and Paschal, 2004; Song and Gelmann, 2005; Kumar et al., 2006; Amazit et al., 2007; Arnett-Mansfield et al., 2007; Griekspoor et al., 2007; Klokk et al., 2007). However, receptors bound to pure antagonists are also mostly nuclear but remain homogeneously distributed in the nucleoplasm and are neither transcriptionally active nor form such nuclear foci. Figure 1 shows a typical dynamic response of AR (androgen receptor) that is reflected in its intracellular distribution during interphase and mitotic phase subsequent to the treatment with an agonist or a pure antagonist. NR-mediated gene expression is modulated by a multitude of accessory proteins that facilitate the assembly of a functional transcription pre-initiation complex. These include the p160 family of co-activators, which interact selectively with the agonist-bound form of NR. In turn, the p160 family members act as molecular scaffolds that attract the enzymes and factors necessary for chromatin modification and remodelling (Stenoien et al., 2000; Baumann et al., 2001; Karvonen et al., 2002; Black et al., 2004; Black and Paschal, 2004; Song and Gelmann, 2005; Amazit et al., 2007; Arnett-Mansfield et al., 2007; Klokk et al., 2007). Notable among the modifying enzymes are the histone acetyltransferases like CBP [CREB (cAMP response element binding protein)-binding protein]/p300. Subsequent co-expression studies of NRs with the p160 family members, p300 and some of the co-activators or basal transcription factors like SRC-1 (steroid receptor co-activator 1), GRIP1 (glucocorticoid receptor-interacting protein 1)/TIF2 (transcriptional intermediary factor 2)/SRC-2, SRC-3 and CBP etc., have shown that these factors co-localize in nuclear foci with agonist-activated NRs (Stenoien et al., 2000; Baumann et al., 2001; Tomura et al., 2001; Karvonen et al., 2002; Saitoh et al., 2002; Black et al., 2004; Black and Paschal, 2004; Song and Gelmann, 2005; Kumar et al., 2006; Amazit et al., 2007; Arnett-Mansfield et al., 2007; Klokk et al., 2007). Recently, using BrUTP incorporation experiments on liver cell line Hep3B that stably expresses GFP (green fluorescent protein)–AR, Houtsmuller's group has shown that AR nuclear foci (or speckles) overlap the sites of active transcription only partially (van Royen et al., 2007). However, the visible nuclear foci are more in number as compared with authentic nuclear foci with active transcription, indicating that AR may also partially associate non-specifically while scanning for the specific binding sites. Thus, agonist-generated nuclear foci in interphase cells have been suggestive of multi-protein complexes that are required for modulation of expression of ligand-responsive genes. Furthermore, emerging evidences are indicating that some of the major cellular proteins having direct or indirect roles in gene transcription regulation remain associated with condensed chromatin during mitosis (Mo and Beck, 1999; Tang and Lane, 1999; Dey et al., 2000, 2003; Sciortino et al., 2001; Chen et al., 2002; Christova and Oelgeschläger, 2002; Pallier et al., 2003; Harrer et al., 2004; Burke et al., 2005; Saradhi et al., 2005; Xing et al., 2005; Das et al., 2006; Velasco et al., 2006; Kobayashi et al., 2006; Yan et al., 2006; Carriere et al., 2007; Young et al., 2007; Cherukuri et al., 2008; Blobel et al., 2009; Verdeguer et al., 2010). These include C/EBP (CCAAT/enhancer-binding protein), topoisomerase II, NF-Y (nuclear factor Y), TBP (TATA-box binding protein), TFIID (transcription factor IID), bromodomain protein, MCAP (mitotic chromosome-associated protein), HMG (high mobility group) proteins (HMGB1, HMGB2, HMGA1a and HMGN), HSF2 (heat shock transcription factor 2), UBF (upstream binding factor), RNA polymerase I, insulator protein CTCF, co-activator PC4, transcription factors FoxI1, Runx2, HNF-1β (hepatocyte nuclear factor-1β), MLL (mixed lineage leukaemia), IL-3 (interleukin-33), BS69 and calreticulin, etc. Concurrently, docking of some NR members [androgen, oestrogen and PXR (pregnane X receptor)] on to the condensed chromosomes during mitotic stages is also reported (Saradhi et al., 2005; Kumar et al., 2008). More interestingly, results from live-cell imaging revealed that agonist-induced nuclear foci formed during interphase co-migrate with condensing chromatin and are clearly visible during early stages of mitosis. However, after metaphase the nuclear foci engulfed during chromatin condensation are not resolved as discretely, probably due to extreme compaction of chromatin (Kumar et al., 2008). Although fewer, there are evidences to suggest that even during chromatin condensation, some target gene promoters remain exposed and accessible to interacting proteins (Sciortino et al., 2001; Christova and Oelgeschläger, 2002; Burke et al., 2005; Chen et al., 2005; Xing et al., 2005, 2008; Yan et al., 2006; Young et al., 2007; Blobel et al., 2009; Verdeguer et al., 2010). Sciortino et al. (2001) have shown that in mammalian cells cyclin B1 transcription occurs even during mitosis where the cyclin B1 promoter retains an open conformation for occupancy by transcription executing factors. Indeed, they have provided in vivo evidence to show that the cyclin B1 promoter is accessible to restriction endonucleases and interacts with transcription factors during mitosis. In addition, by formaldehyde cross-linking and immunoprecipitation assays they have demonstrated that NF-Y is bound to the cyclin B1 promoter during mitosis (Sciortino et al., 2001). Conceivably, the presence of promoter encompassing pits within condensed mitotic chromatin and dynamic docking of transcription factors on to these platforms should have important physiological ramification.
2. BIOPIT (biomolecular imprints offered to progeny for inheritance of traits) model and epigenetics: two sides of the same coin
In contemporary biology, epigenetic regulatory processes govern chromatin structure and gene expression through covalent modification of DNA, RNA and histone substrates via methylation, acetylation, phosphorylation or ubiquitination processes that are collectively termed as epigenetic markings (Goldberg et al., 2007; Kouzarides, 2007). In simple analogy to these epigenetic regulatory processes, biomolecular marking by ligand-activated transcription factors can also be broadly defined as an alternate mechanism utilized by proliferating cells in transmitting the pattern of active gene transcription from interphase nucleus, via mitosis, to the emerging progeny cells. However, cell transverse mitosis in apparently transcriptionally silenced state. Ensuing events appear to imply that cells inherit only a biomolecular blueprint of active transcription status with transcription factors associated with mitotic chromatin while some modulatory factors (GRIP1, SRC-3, etc.) abort the transcription complex (Kumar et al., 2008). Operation of such a mechanism, therefore, is expected to ensure ideal transmission of an exclusive blueprint of active transcription status over to next generations that help in initiating an identical gene expression profile for sustenance of characteristic cellular proteome.
With respect to ligand-modulated transcription factors, this feed-forward transmission over the generations, by receptors themselves, may also encounter active transcription pattern modifications depending on appearance and disappearance of physiological ligands during developmental stages or aging processes. However, under normal cell proliferation conditions retention and transmission of biomolecular imprints of active genes from the progenitor to progeny is expected to help in maintenance of the inherent cellular characteristics and cell phenotype. For example, when working with cultured cell lines, experience has shown that a population of breast/prostate cancer line even after passaging for a long time will always emerge as itself rather than any other cell or tissue type. To distinguish from epigenetic marking the act of BIOPIT via transcription factors themselves can be explained by BIOPIT model or by their act of BIOPIT-ing (Figure 2). The BIOPIT model is demonstrated in Figure 2(A) by citing an example of an NR represented by unliganded and ligand-activated AR in live cells. Subsequently, the phenomenon is vividly explained by a schematic cartoon in Figure 2(B). Support for the model is apparent from the observations made with some of the major NRs [AR, ERα (oestrogen receptor α) and PXR] (Saradhi et al., 2005; Kumar et al., 2008) and other basal transcription factors belonging outside the NR superfamily (Chen et al., 2002; Christova and Oelgeschläger, 2002; Burke et al., 2005; Xing et al., 2005, 2008; Yan et al., 2006; Young et al., 2007, Blobel et al., 2009; Verdeguer et al., 2010).
The predictions supporting the BIOPIT model at molecular level that have been derived from emerging literature are consolidated in Figure 2(B). In the light of the existing literature and the experiments supporting the BIOPIT model, it is reasonable to hypothesize that ligand-activated AR resides on AREs (androgen response elements) of its target genes. The model implies that within the extremely compact mitotic chromatin regions of genomic DNA, loosely compact chromatin with exposed AR-regulated promoters and enhancers that are accessible to AR may be present. Mutations in the DNA-binding domain of AR have indicated that this receptor binds specifically to its response elements on mitotic chromatin (Kumar, 2010). Moreover, it has been shown that NRs including AR are dynamically associated with the interphase chromatin (Klokk et al., 2007, and references therein). In this context, we have observed that AR and PXR dynamically associate not only with interphase chromatin but also with mitotic chromatin (Kumar, 2010). These observations appear to indicate that NR-interacting sites on mitotic chromatin may be perpetually exposed to conserve this dynamic bonding between interacting molecules. Recently, Brown's group have shown that during interphase AR binds on numerous binding sites in the whole genome of LNCaP and abl cell lines (Wang et al., 2009). Therefore, it is reasonable to speculate that AR (or NRs) may be executing hitherto unknown functions on mitotic chromatin that are analogous to histone epigenetic marks. In addition, it is possible that ligand-activated AR bookmarks its regulated genes by recruiting phosphatase PP2A on specific promoters and subsequently allows efficient dephosphorylation/inactivation of condensins by PP2A to inhibit compaction of promoter regions. Similar studies of gene bookmarking by HSF2 and TBP support the above speculations (Xing et al., 2005, 2008). In case of HSF2 and TBP, both the proteins interact with PP2A and condensins and recruit PP2A to the promoter regions to dephosphorylate condensin and inhibit chromatin condensation (Xing et al., 2005, 2008). It is documented that AR interacts with PP2A in ligand-dependent fashion during interphase (Yang et al., 2007), but it is still uncertain whether AR interacts with PP2A during mitosis. It needs to be investigated if AR and other NRs also interact with PP2A and condensins during mitosis to inhibit the compaction of their promoters regions. At this stage we can clearly speculate that NRs bind to the mitotic chromatin at specific enhancers and promoters of their target genes and simultaneously TBP and other associated factors also remain bound to the mitotic chromatin at the TATA box. As the cell exits mitosis other components of the transcription machinery assemble to accelerate the transcription of highly active genes.
The suggested BIOPIT model needs to be further validated by several experimental approaches. First, genome-wide recruitment studies of NRs interacting with specific nucleotide sequences of promoters and enhancers of NR-regulated genes during mitosis may be performed in asynchronous and synchronous cell lines using ChIP (chromatin immunoprecipitation), genome-wide ChIP on ChIP and ChIP-sequencing experiments. Secondly, the expression and activity of NR-regulated genes in control and NR knockdown cell lines should be measured after the cells exit the mitosis. Genome-wide location analysis will reveal the occupancy of NRs on to promoters and enhancers of their regulated genes during mitosis. Knockdown experiments are expected to make it explicit whether NR retention at multitude gene promoters and enhancers during mitosis accelerate transcription reactivation following mitotic exit or not.
3. Implications of eradication of BIOPIT markings
Based on the concept of BIOPIT model, we can explain how therapeutic drugs and endocrine disruptors that target NRs may actually alter the inheritance of cell's transcription memory leading to unwarranted physiological consequences. Conceivably, during anti-hormone therapy (as in the case of breast/prostate cancer) or consistent exposure to hormone-mimicking endocrine disruptors can alter the natural BIOPIT-ing process over many generations that may inflict upon target cells to undertake alternative survival strategies (Tyagi, 2003; Kumar et al., 2008). Such consistent chemical pressures may lead to the emergence of a new genre of cells that will trounce the inflicted chemical stress and thereafter proliferate uninterruptedly. In this perspective, recurrence of advanced stages of cancers from hormone-dependent to hormone-independent stage when undergoing anti-hormone therapy may be a consequence of inflicted turbulences in natural BIOPIT-ing process. In brief, the present BIOPIT model is expected to offer a novel paradigm in explaining the concerted action and consequences of ligand–receptor interactions in the perspective of normally sustained physiology and clinically aberrant situations (Kumar et al., 2008; Chaturvedi et al., 2010).
Sanjay Kumar performed most of the experiments, and captured and analysed the images from fluorescence microscopy. He also contributed by making the manuscript figures and assembling the literature related to the subject. Initial experiments related to association of NRs, PXR and AR with mitotic chromatin were performed by Mallampati Saradhi and Nagendra Chaturvedi respectively. The BIOPIT model and manuscript was developed by Rakesh Tyagi.
S. Kumar and N. K. Chaturvedi acknowledge CSIR (Council of Scientific and Industrial Research) for the award of Research Fellowships. M. Saradhi was supported by a fellowship from ICMR (Indian Council of Medical Research), India.
This work was supported by
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Received 23 October 2009/10 June 2011; accepted 18 October 2011
Published as Cell Biology International Immediate Publication 18 October 2011, doi:10.1042/CBI20090329
© The Author(s) Journal compilation © 2012 Portland Press Limited
ISSN Print: 1065-6995
ISSN Electronic: 1095-8355
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