Diverse Roles Of Nuclear Intermediate Filaments In Proliferating Cells
Embryonic tissues and cancer have in common the fact that they are both highly proliferative tissues rapidly moving through the cell cycle, as opposed to most other differentiated tissues in an adult. DNA damage can arrest some embryonic cells but genetic instability is a hallmark of cancer. This thesis studies the contrasting role of two nuclear intermediate filaments - Lamin A and Lamin B1 in the proliferating cells of embryonic hearts and cancer. Lamin B1 is upregulated together with proliferation genes in at least 15 cancers curated in The Cancer Genome Atlas (TCGA), whereas Lamin A trends align with ‘matrix mechanosensititve’ genes. With physicochemical principles in mind, we show Lamin B1 scales with many mitosis genes in cancer, and experiments reveal its role in promoting cell cycle and direct regulation by the cell cycle transcription factor FOXM1. The genes that scale are used in Scaling-informed Machine Learning (SIML) to better predict overall patient survival and to better identify cell lineage in single cell RNA profiles. A distinct role of Lamin A is revealed by experiments on the first organ in its first days – the heart – which show Lamin A levels are modulated in interphase cells through phosphorylation in response to acto-myosin stress. Lamin A levels determine the probability of nuclear rupture and subsequent DNA damage, telomere attrition, and cell cycle arrest. Nuclear lamins thus have different roles in responding to and regulating cell cycle.