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Eury Bonn Villanueva 10-Rutherford

The document discusses how scientists have provided an explanation of how chromosomes undergo structural changes during cell differentiation. It describes how chromosomes are organized into topological associating domains and A/B compartments, and how these compartments change between cell types and during differentiation, correlated with changes in gene expression and replication timing. The study observed these compartment changes in differentiating mouse embryonic stem cells at the single-TAD level.

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20 views

Eury Bonn Villanueva 10-Rutherford

The document discusses how scientists have provided an explanation of how chromosomes undergo structural changes during cell differentiation. It describes how chromosomes are organized into topological associating domains and A/B compartments, and how these compartments change between cell types and during differentiation, correlated with changes in gene expression and replication timing. The study observed these compartment changes in differentiating mouse embryonic stem cells at the single-TAD level.

Uploaded by

hanifa rebanza
Copyright
© © All Rights Reserved
Available Formats
Download as DOCX, PDF, TXT or read online on Scribd
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EURY BONN VILLANUEVA 10- RUTHERFORD

How chromosomes change their shape during cell differentiation.

Date: October 9, 2019

Source: RIKEN Summary: Scientists have provided an explanation of how


chromosomes undergo structural changes during cell differentiation.

The human genome is made up of 46 chromosomes, each of which has a length of


about 100-200 million base pairs, base pairs being the building blocks of the DNA
double helix. Even during interphase, the period in between the cell division
phases, chromosomes are still tightly packed inside the cell nucleus. If one zooms
in on each chromosome, a regular structural unit called the nucleosome is
evident, which corresponds to a 146-base pair long strand of DNA wrapped
around eight histone protein molecules. Until recently, no other regular
structures beyond the nucleosomes were known. Thanks to the emerging
genomics-based technology called Hi-C (high-throughput chromosome
conformation capture), however, we now know that there are regular structural
units at the megabase scale, referring to millions of base pairs. It is now generally
accepted that mammalian chromosomes are comprised of megabase-sized
globular units called topologically associating domains (TADs), which are
separated by boundaries, presumably in a beads-on-a-string manner. Further,
multiple TADs assemble to form what are called A and B subnuclear
compartments. TADs containing many active genes form A compartments, while
TADs with few or no active genes form B compartments. It is generally believed
that TADs are stable units of the chromosomes and that their boundary positions
do not change between cell types. By contrast, the organization of A/B
compartments differs between cell types, meaning that the boundaries between
them change during differentiation. However, nobody has ever observed changes
in A/B compartments as they occurred. Scientists from the RIKEN Center for
Biosystems Dynamics Research have now observed A/B compartment changes in
detail during the differentiation of mouse embryonic stem cells (mESCs). They
discovered many genomic regions that switched compartments, either from A to
B or vice versa, which, interestingly, correlated well with the genomic regions that
switched their replication timing (the temporal order of genomic DNA replication)
from early to late or vice versa, respectively. A to B compartment changes were
accompanied by movements from the nuclear interior to the periphery and by
gene repression, while B to A compartment changes were accompanied by
movements from the nuclear periphery to the interior and by gene activation.
These results strongly suggest that A/B compartment changes represent physical
movements of portions of chromosomes within the 3D nuclear space,
accompanied by changes in gene expression and replication timing. Regarding the
temporal relationship between the physical movements of chromosomes and
changes in gene expression and replication timing, the research team found that
genomic regions that switched from B to A compartment clearly did so one to two
days prior to gene activation, and that the changes in replication timing were
from late to early. This raised an intriguing possibility that compartment changes
might be a prerequisite for gene activation and replication timing changes. The
team went on to characterize the features of genomic regions that changed A/B
compartments. Compartments were found to change primarily by the shifting of
A/B compartment boundaries, while the emergence of new compartments -- for
example the emergence of an A compartment within a stretch of B compartment
or vice versa -- was rare. Because compartment boundaries corresponded to a
subset of TAD boundaries, they looked at how many TADs changed compartments
and discovered that the majority of the changes affected single TADs.
Importantly, this single-TAD-level switching of compartments was confirmed in
single cells by a method, called single-cell Repli-seq, which was recently
developed by the research team to analyze DNA replication regulation genome-
wide in single cells (note that replication timing correlates very well with A/B
compartments). The team also found that A/B compartment profiles changed
gradually but uniformly within a differentiating cell population, with the cells
transiently resembling the epiblast-derived stem cell (EpiSC) state, an advanced
form of stem cells compared to ESCs. Taken together, the team's finding suggests
that A/B compartments change primarily by the relocation of single TADs facing
the A/B compartment interface to the opposite compartment. "It is possible,"
says Ichiro Hiratani, the leader of the group, "that the accumulation of these
compartment switching events may reflect or represent changes in differentiation
states such as from ESCs to EpiSCs." In this way, this study, published in Nature
Genetics, explains how chromosomes undergo structural changes during cell
differentiation. According to Hiratani, "Our study was the first to clearly
demonstrate that changes in chromosome conformation preceded changes in
DNA-based transactions such as gene expression and DNA replication timing.
Intriguingly, chromosome conformation changes were regulated at the level of
single TADs. We are eager to explore the basis of such single-TAD-level regulation
of chromosomes and entertain the possibility of predicting DNA transactions
based on preceding changes in chromosome structures.

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