Retention and transmission of active transcription memory from progenitor to progeny cells via ligand‐modulated transcription factors: elucidation of a concept by BIOPIT model

Abstract

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.

Current Insights and Advancements in Head and Neck Cancer: Emerging Biomarkers and Therapeutics with Cues from Single Cell and 3D Model Omics Profiling

“…In order to sustain the inheritance of gene expression and biological functions, epigenetic mechanisms are linked to the transmission of cell lineage and phenotype from progenitor to progeny. These modifications are now known to be transmitted to the progeny cells with the epigenetic marks or genome bookmarking by transcription factors and other gene regulatory proteins ( 137 , 138 ). The deviation from the transmission of normal epigenetic marking is suggested to be relevant not only in cell differentiation but also in the onset of several diseases, including cancer.…”

Potential Gene Interactions in the Cell Cycles of Gametes, Zygotes, Embryonic Stem Cells and the Development of Cancer

“…Toxicants include industrial chemicals, such as dioxine and polychlorite biphenyles pesticides, and pharmaceutical products, e.g., cytostatic drugs that block gene transcription and may cause permanent damage in blastocysts. Even pre- and peri-conceptional exposures are associated with disease in the offspring through interfering with meiotic and/or mitotic cell cycles ( 10 , 11 ). For example, alterations of temporal and spatial patterns of meiotic DNA replication are induced through involvement of proteins SMC1β, RAD21L, and STAG3 of the TET1-regulated replication machinery by complex cohesion links between meiosis and ­cancer ( 12 ).…”

Androgen receptor association with mitotic chromatin – analysis with introduced deletions and disease‐inflicting mutations

“…Considering that these residues serve a role in both acetylation and binding to importin‐α, it is important to explore how mutations within this region and other parts of the hinge region of AR influence the subsequent association with mitotic chromatin. Determination of the mechanism for the mitotic chromatin association of AR and its mutants will not only provide us with the potential targets of androgen‐mediated regulation, but also contribute to our understanding of the influence that androgens have on AR‐related diseases .…”

“…It was postulated that the docking of NRs to the condensed mitotic chromatin platform has important physiological ramifications. In this context, gene book‐marking and BIOPIT (biomolecular imprints offered to progeny for inheritance of traits) hypotheses were proposed to explain the physiological significance of the mitotic chromatin association of transcription factors . It was reported that, during mitosis, ‘interphase nuclear foci’ co‐migrate with condensing chromatin as transcription units to the progeny cells, ensuring that the progenitor cells transmit a biomolecular blueprint of transcription status to subsequent generations to express and sustain their characteristic proteome .…”

“…It was reported that, during mitosis, ‘interphase nuclear foci’ co‐migrate with condensing chromatin as transcription units to the progeny cells, ensuring that the progenitor cells transmit a biomolecular blueprint of transcription status to subsequent generations to express and sustain their characteristic proteome . The ‘biopit model’ attempted to explain how the disruption of ‘biopit markings’ by therapeutic anti‐hormones or endocrine disruptors over prolonged periods may lead to an erosion of cellular transcription memory with deleterious cellular consequences . Although the binding of ligand‐activated AR to mitotic chromatin during mitosis has been reported , there are several questions that warrant detailed investigation.…”