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Cell Fate: Another Hurdle for Evolution

David Coppedge
Photo: Neutrophils, by Dr Graham Beards, CC BY-SA 3.0 , via Wikimedia Commons.

When a stem cell divides, one daughter cell must maintain its stemness (i.e., ability to differentiate into any cell type) while the other specializes. Therein lies another truckload of requirements for coordinated action that, if it goes awry, can spell disaster for an animal or human. Watch this subject grow into a huge problem for evolutionary theory.

Researchers at University of California at Riverside investigated what happens when stem cells divide and specialize. UCR’s reporter Iqbal Pittawala describes how “genome organization influences cell fate.”

Understanding the molecular mechanisms that specify and maintain the identities of more than 200 cell types of the human body is arguably one of the most fundamental problems in molecular and cellular biology, with critical implications for the treatment of human diseases. Central to the cell fate decision process are stem cells residing within each tissue of the body. [Emphasis added.]

The two daughter cells face a massive organization problem. Even though they contain the same DNA code, they will take on separate roles in the cell. This means that the accessibility of genes between the two cells must radically differ. 

Chromatin — a package of DNA wrapped around histone proteins — makes some genes accessible for transcription but hides others from the transcription factors (additional proteins) that switch on transcription. Begin to get a sense of how difficult this will be. There are tens of thousands of genes, and 200 cell types that utilize specific genes but not others. What process determines how chromatin will package the specialist daughter cell to make genes available if it will be a nerve cell as opposed to a muscle cell or heart cell? And how does the system keep the other daughter cell unaltered from the original stem cell?

A Challenge for a Librarian

Biochemist Sihem Cheloufi at UCR, together with colleague Jernej Murn, researched a protein complex involved in the process named “chromatin assembly factor 1” or CAF-1. As you read their description, think of the challenge a librarian faces with the card catalog for a large library.

“To help CAF-1 secure correct chromatin organization during cell division, a host of transcription factors are attracted to open regions in a DNA sequence-specific manner to serve as bookmarks and recruit transcription machinery to correct lineage-specific genes, ensuring their expression,” she said. “We wondered about the extent to which CAF-1 is required to maintain cell-specific chromatin organization during cell division.”

CAF-1 normally keeps genes tightly bound in chromatin so that they are inaccessible to transcription factors. 

For a specific case, the biochemists looked at how blood stem cells divide and specialize into neutrophils — a type of white blood cell that acts as a first responder against an invasion by pathogens. They noticed that the levels of CAF-1 are finely balanced to prevent access by a particular transcription factor for that lineage named ELF1. (Note in passing that each cell type has its own suite of lineage-specific transcription factors.) Neutrophils artificially deprived of CAF-1 went awry and forgot their identity.

“By looking at chromatin organization, we found a whole slew of genomic sites that are aberrantly open and attract ELF1 as a result of CAF-1 loss,” Murn said. “Our study further points to a key role of ELF1 in defining the fate of several blood cell lineages.”

Peeking into a Keyhole

Recalling the 200 cell types in the human body, how does CAF-1 organize chromatin for each type? How does it know what genes to make accessible for a kidney cell, an astrocyte in the brain, or a liver cell? The UCR work is peeking into a keyhole of a library with a big operation inside. They don’t yet know how CAF-1 “preserves the chromatin state at specific sites and whether this process works differently across different cell types.” Think of our librarian just starting to get a handle on the job of arranging books in one wing and then finding 200 more wings to manage. Maybe a different analogy will expose the magnitude of this challenge.

Like a city, the genome has its landscape with specific landmarks,” Cheloufi said. “It would be interesting to know how precisely CAF-1 and other molecules sustain the genome’s ‘skyline.’ Solving this problem could also help us understand how the fate of cells could be manipulated in a predictive manner. Given the fundamental role of CAF-1 in packaging the genome during DNA replication, we expect it to act as a general gatekeeper of cellular identity. This would in principle apply to all dividing cells across numerous tissues, such as cells of the intestine, skin, bone marrow, and even the brain.

Surely there is much, much more involved than one protein complex named CAF-1. Something needs to “know” how to keep one daughter cell’s chromatin unchanged to maintain the stem cell pool, while reorganizing the chromatin for the differentiating cell — assuming the system also “knows” what cell type that daughter cell must become out of 200 possibilities. This implies a complex signaling system for triggering the production of specific cell types, which must trigger the appropriate suite of protein complexes to package the chromatin for access by that cell type’s lineage-specific transcription factors. Differentiation proceeds down a stepwise transition through progenitor cell states until the specialized cell, such as a neutrophil, results. How many evolutionists have thought about this challenge?

Quality-Control Terms from Engineering

The research paper is published open access. It is Franklin et al., “Regulation of chromatin accessibility by the histone chaperone CAF-1 sustains lineage fidelity,” in Nature Communications. Perhaps the magnitude of the challenge caused the 21 authors to shy away from referring to evolution in the paper. Instead, they refer to “lineage integrity” or “lineage fidelity” a dozen times. Those are quality-control terms from engineering and systems design.

Cell fate commitment is driven by dynamic changes in chromatin architecture and activity of lineage-specific transcription factors (TFs). The chromatin assembly factor-1 (CAF-1) is a histone chaperone that regulates chromatin architecture by facilitating nucleosome assembly during DNA replication. Accumulating evidence supports a substantial role of CAF-1 in cell fate maintenance, but the mechanisms by which CAF-1 restricts lineage choice remain poorly understood. Here, we investigate how CAF-1 influences chromatin dynamics and TF activity during lineage differentiation. We show that CAF-1 suppression triggers rapid differentiation of myeloid stem and progenitor cells into a mixed lineage state. We find that CAF-1 sustains lineage fidelity by controlling chromatin accessibility at specific loci, and limiting the binding of ELF1 TF at newly-accessible diverging regulatory elements. Together, our findings decipher key traits of chromatin accessibility that sustain lineage integrity and point to a powerful strategy for dissecting transcriptional circuits central to cell fate commitment.

Expecting random mutations to somehow emerge then be “selected” by some blind, aimless, uncaring “agentless act” (as Neil Thomas has put it) to construct this complex system seems beyond rational consideration. Intelligent design scientists, though, could make testable predictions to guide further research. Knowing how comparable systems are made by intelligent engineers — that is, systems involving coordinated reorganization of information for multiple applications — they could expect to find new types of sensors, feedback circuits, quality-control checkpoints, or other functional modules at work. These might consist of proteins, protein complexes, small RNAs, sugars, ions, or combinations of them capable of storing or conveying information. (Note: even if automated, these are not “agentless acts.” The agency is one step removed from mind to program, but a mind with foresight was necessary for its origin.)

For example, an ID research team might look for a comparable system in industry that faces the same kind of challenge. They could identify the minimum number of job descriptions required to make the system work, then look for molecules performing those roles in the cellular analogue. Even if the match is imperfect, the ID approach can advance science, because what the researchers learn can feed back into biomimetic design, leading to improved applications in industry. 

Poor Darwin. With his crude awareness of cells dividing that looked like bubbles separating, he had no idea what he would be in for in the 21st century.