Cellular Memory Mechanisms and Differentiation

Mechanisms of Cellular Memory

• Cellular differentiation is irreversible; once a cell differentiates, it retains that state even without external signals.
• Chromatin remodeling plays a role; DNA methylation and histone modifications are copied to daughter cells.

Positive Feedback Mechanisms in Differentiation

• Positive feedback describes a self-amplifying loop: an external signal triggers a process that strengthens itself.
• Involves master gene regulators (transcription factors controlling specific genes) regulating the production of more of themselves (e.g. MITF for melanocytes, MYOD1 for skeletal muscle). This cycle maintains the differentiation state even when the initial signal stops.

Melanocyte Differentiation

• Melanocytes are pigment-producing cells in the skin's epidermis.
• Melanocyte stimulating hormone (MSH) and its receptor (MC1R) initiate a signaling cascade.
• Cyclic AMP production and activation of MITF (transcription factor), then CREB, lead to the transcription of genes related to melanin production.

MITF and Melanocyte-Specific Genes

• MITF production leads to increased production of MC1R and ongoing melanin production, even without continuous MSH stimulation.
• A basal level of MC1R activity exists, ensuring melanocyte function even in the absence of MSH.

Microphthalmia-Associated Transcription Factor (MITF)

• MITF mutations in mice can lead to the absence of melanocytes, causing small eyes (microphthalmia).
• Mutations in MITF are associated with human conditions like Waardenburg syndrome type 2, which involves pigment loss in skin and possibly eyes and can also cause hearing related problems.

Key Transcriptional Regulators of Skeletal Muscle

• The myogenic factors (MYOD1, MYF5, MYOG, MRF4) are master regulators controlling skeletal muscle differentiation.
• They often work with E proteins in dimers to initiate transcription.
• ID1, an inhibitor of differentiation, can block this process.

MYOD Family, E Proteins, and ID1

• In normal muscle development, myogenic factors and E proteins work together to promote transcription.
• ID1 can bind to E proteins and prevent their interaction with the myogenic factors.
• Environmental factors (e.g., reduced growth factors like FGF and IGF) cause ID1 destabilization, leading to muscle differentiation.

Skeletal Muscle Differentiation in Embryos (Simplified)

• Myoblasts migrate to muscle formation sites.
• Myoblasts express MYOD1, MYF5, ID1, and E proteins.
• Reduced FGF and IGF signals cause ID1 destabilization.
• Positive feedback from the myogenic factors initiates muscle gene expression through E protein activation and transcription.

Cell Senescence

• Cell senescence is the permanent halt in cell division after extended proliferation.
• Senescent cells play a protective role against cancer.
• Key characteristics of senescent cells include morphological changes (e.g., larger cells, prominent nucleoli), increased lysosomal beta-galactosidase, and the presence of cell cycle inhibitor protein p16.

Telomeres

• Telomeres are repetitive DNA sequences (TTAGGG) at chromosome ends.
• They protect chromosomes from deterioration and fusion.
• Telomeres shorten with each cell division.

Telomerase

• Telomerase is an enzyme that maintains telomere length by adding telomeric repeats.
• It's active in germ cells to maintain telomere length.
• Most somatic cells do not express telomerase, causing telomere shortening.

Telomeres, Senescence, and Cancer

• Cancer cells often reactivate telomerase, which leads to immortality.
• Senescence acts as a barrier against uncontrolled cell division.
• Cancer cells often circumvent or evade senescence mechanisms.

Established Cellular Senescence Pathways

• P53, p16, and p21 are senescence pathways that can inhibit cyclin-dependent kinases and halt cell growth.
• Deficiencies in senescence pathways can contribute to cancer development.

Senescence and Ageing

• Telomere shortening is associated with aging.
• Senescence-associated proteins (like p16) increase with age.
• Defective telomerase subunits can cause premature aging and disease.
• Genetic links exist between p16 locations and various aging-related medical issues such as cardiovascular conditions, type 2 diabetes, frailty and cancer.

Stem Cells

• Stem cells are cells with self-renewal and differentiation potential.
• Different types of stem cells exist (totipotent, pluripotent, unipotent)
• Somatic stem cells exist post-nataly. They also self-renew.
• Stem cell senescence contributes to age-related decline in tissues like bone marrow and skin. Stem cells also contribute to ageing.

This quiz explores the mechanisms of cellular memory and the processes involved in cellular differentiation. It covers topics such as chromatin remodeling, positive feedback mechanisms, and the specific differentiation of melanocytes. Understand the role of transcription factors and signaling pathways in maintaining differentiated states.