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If I understand correctly, as stem cells divide, they become more and more specialized. The very first (fertilized) cell still can divide into every other cell in the body, but as they divide further, each cell can divide only into a smaller subset of different cell types.

However, it seems that (other than gametes) each cell contains the full genome, an identical copy of the entire DNA. So if the DNA does not get altered as cells specialize, how does a cell keep track of which parts of that DNA it is supposed to read - and how does it tell its daughter cells to change their specialization when it divides?

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  • $\begingroup$ This is the age-old question. Since DNA encodes all the data for growth and differentiation of cells, and since every cell; contains essentially the same complement of DNA, how does each cell differentiate from others? In the usual answer, reference is made to transcription factors and epigenetic factors etc., but since these must also be encoded in DNA itself, the essential question remains. Eventually reason demands some sort of deterministic approach and a corresponding mechanism. One might propose -- and I know that this site is averse to such conjecture --... $\endgroup$
    – jeremiah
    May 20, 2022 at 7:42
  • $\begingroup$ .. one might propose a wave dynamic in which not only is DNA itself, its structure and chemical constituents -- its entire substance, in common with the rest of reality-- the function of a fundamental 'wave interference effect', but both its mechanisms of replication and transcription conform to the progressive aspect of such an oscillatory wave principle. An incremental advance in the property of wave recurrence both within the pattern of transcription itself and in its cell-to-cell aspect would permit both features of the phenomenon of cell differentiation: that each cell derives its own... $\endgroup$
    – jeremiah
    May 20, 2022 at 7:51
  • $\begingroup$ .. each cell derives its own characteristic and definitive set of both basic and more-or-less specialised proteins and that successive cells in contiguous relation to each other derive proteins which differ slightly in conformation and definitive identity as this wave effect progresses incrementally from cell-to-cell; this latter aspect in particular implicating the requisite production of transcription factors etc. commonly encoded in all DNA. Clearly such an idea requires some substantial modification of what is eventually the philosophical approach to scientific inquiry, of its paradigm. $\endgroup$
    – jeremiah
    May 20, 2022 at 8:09

2 Answers 2

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The process of "specialization" is usually referred to in biology as "differentiation".

Largely, differentiation is a function of expression of transcription factors; these proteins determine which proteins are synthesized in a given cell by either promoting or suppressing transcription. Transcription factors can also influence the transcription of transcription factors themselves. Simplifying things a bit, imagine you have a "muscle cell" transcription factor, we'll call it "MCTF", that is only expressed in muscle cells. MCTF binds to DNA and causes transcription of muscle-related genes, including MCTF itself. It also causes transcription of not-a-neuron transcription factor ("NNTF"); NNTF binds to DNA and prevents transcription of neuron-related genes.

Epigenetic modification including DNA methylation and histone modification can also silence sections of the genome to make cell fate a bit more concrete and less likely to revert.

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    $\begingroup$ Thanks! So is the emergence of a new transcription factor that specializes the cell based on some probabilistic process? Like if an "arm cell transcription factor" is present on each division a cell will produce with some probability a "hand cell transcription factor"? Or how are new transcription factors introduced into daughter cells that weren't present in the parent cell? $\endgroup$
    – matthias_buehlmann
    May 18, 2022 at 21:46
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    $\begingroup$ @matthias_buehlmann That's quite complicated and too much to talk about in a single SE answer, I feel. A textbook on developmental biology would be a good place to start. Very generally, in early embryonic development there are some push-and-pull stochastic relationships, where certain molecules might signal "head" or "front" and others "tail" or "back"; "head" makes more "head" and suppresses "tail"; "tail" does vice-versa. What starts out unstable very quickly reaches an equilibrium where "head" and "tail" are clearly separate. Something similar happens at local scales, as well. $\endgroup$
    – Bryan Krause ♦
    May 18, 2022 at 22:07
  • $\begingroup$ @matthias_buehlmann en.wikipedia.org/wiki/Cell_fate_determination is another place to start reading. $\endgroup$
    – Bryan Krause ♦
    May 18, 2022 at 22:07
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Transcription factors usually initiate the cellular changes, but it's mostly the chromatin state of the nucleus that maintains the state of a cell and stops it from changing back and forth.

Embryonic stem cells start out with open chromatin ('open' means 'accessible'). This means low DNA methylation and overall epigenetic modifications that enable transcription. This can be interpreted as "a cell with full potential", since many regions on the DNA are available for transcription.

The further a cell differentiates, the more DNA regions assume a closed chromatin state, meaning higher DNA methylation and repressive epigenetic marks that lead to DNA condensation. It's as if the 'potential' decreases, since huge regions on the DNA become 'locked up'. These huge regions on the DNA are partitioned into 'TADs' (Topologically Associating Domains) and their epigenetic state can be determined by ATAC-Seq

See this review for reading about chromatin state and stem cells.

As mentioned by Bryan, specific transcription factors are unique to a cell type. Some transcription factors bind to multiple promoter regions and initiate a complex differentiation program that orchestrates cellular/biochemical/morphological changes needed to fulfill specialized function.

The promoters involved in cell differentiation can be in a 'poised' (aka 'bivalent') state, meaning that they got both transciption -inducing (H3K27me3) and -repressing (H3K4me3) epigenetic marks, so it's as if these promoters are "ready and waiting" for a signal to decide whether to transcribe or lock up a DNA-region. And once a DNA region is locked up, the cell knows that it has lost some potential and "knows" what cell type it is. Lesch & Page 2014

Such poised promoters are not just present in embryos, but also in adult tissues, like mesenchymal stem/stromal cells (MSCs) in the bone marrow. The RUNX2 Promoter is poised and is waiting for signals to turn the MSC into an osteoblast (or chondrocyte or adipocyte). Wu et al 2017

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