Questions: Cell Differentiation: Specifying Cell Type

Question 1

A liver cell and a neuron in the same person have dramatically different structures, functions, and gene expression patterns. What is the primary molecular basis for this difference?

• A. Liver cells and neurons contain different subsets of genes, with unwanted genes deleted during development
• B. Different cells express different subsets of the same genome, controlled by transcription factors and epigenetic marks
• C. Neurons have amplified copies of neural genes, while liver cells have amplified copies of metabolic genes
• D. DNA rearrangement during embryogenesis shuffles gene order differently in each tissue type

Answer: (B)

All somatic cells in an organism contain the same complete genome — no genes are deleted, amplified, or rearranged during normal differentiation (with narrow exceptions like immune cells). The difference between cell types is entirely regulatory: which genes are transcribed. Transcription factors bind cell-type-specific enhancers and activate particular gene programs, while epigenetic marks (DNA methylation, histone modifications) maintain those patterns across cell divisions. The genome is the same; the gene expression pattern is different.

Question 2

Yamanaka showed that introducing four transcription factors into adult skin fibroblasts can reprogram them into induced pluripotent stem cells (iPSCs). Which principle does this most directly demonstrate?

• A. Adult cells contain a different genome from embryonic stem cells, and reprogramming restores the original sequence
• B. Differentiation is maintained by epigenetic marks rather than irreversible DNA changes, so resetting those marks can reverse differentiation
• C. The four Yamanaka factors repair DNA damage that accumulated during adult life
• D. Reprogramming only works in skin cells because they are the least specialized cell type

Answer: (B)

The Yamanaka experiment is the clearest evidence that differentiation is a regulatory state, not a genetic one. Adult skin cells have the same DNA as embryonic stem cells. The differentiated state is maintained by epigenetic marks — DNA methylation and histone modifications — that silence pluripotency genes and activate skin-specific programs. Introducing Oct4, Sox2, Klf4, and c-Myc resets this epigenetic landscape, re-activating the pluripotency program. If differentiation involved permanent DNA changes, reprogramming would be impossible — the DNA would be gone. That it works confirms the epigenetic nature of cellular identity.

Question 3

Once a cell differentiates (e.g., into a liver cell), its gene expression pattern is permanently fixed — it can seldom be altered under any circumstances in the adult organism.

• T. True
• F. False

Answer: False

False. While differentiated states are stable and self-reinforcing under normal conditions, they can be reversed. Yamanaka's reprogramming of adult cells into iPSCs is the most dramatic demonstration. Some cells also naturally dedifferentiate in regenerative contexts (e.g., certain amphibian tissues). Epigenetic marks that maintain the differentiated state can be overwritten by sufficiently strong regulatory signals — master transcription factors can override the existing epigenetic landscape. The stability of differentiation comes from the self-reinforcing nature of epigenetic inheritance, not from irreversibility.

Question 4

All somatic cells in a multicellular organism contain the same complete DNA sequence, regardless of their cell type, function, or tissue of origin.

• T. True
• F. False

Answer: True

True. With the exception of immune cells (which undergo V(D)J recombination to generate antibody diversity), all somatic cells arise from the same fertilized egg by mitosis and carry identical DNA sequences. This was established by nuclear transfer experiments (dolly the sheep) and confirmed by Yamanaka's iPSC work. The remarkable diversity of cell types arises entirely from differential gene expression — which genes are turned on or off — not from differences in the underlying genetic sequence.

Question 5

If all cells in an organism have identical DNA, what determines which genes are expressed in each cell type, and how is that pattern of expression maintained when the cell divides?

Model answer: Transcription factors determine which genes are expressed by binding specific DNA sequences (enhancers and promoters) to activate or repress target genes. During development, cells receive signals that activate particular transcription factors, which then switch on cell-type-specific gene programs. This pattern is maintained across cell divisions by epigenetic mechanisms: DNA methylation and histone modifications that alter chromatin accessibility are copied by dedicated enzymes during DNA replication, so daughter cells inherit the same pattern of open and closed chromatin as the parent. Active genes remain accessible; silenced genes stay compacted.

The key insight is that differentiation is a regulatory state encoded in the epigenome, not the genome. The genome is the same in all cells — what differs is the chromatin landscape layered on top of it. Master transcription factors initiate differentiation; epigenetic inheritance maintains it. This is why a liver cell's daughters are liver cells: the epigenetic marks that define liver-specific gene expression are faithfully propagated at every division, even though the DNA sequence that could express any gene remains intact.