YSM Issue 95.2

FOCUS
Spatial Transcriptomics / Chemistry
SCANNING DNA
BARCODES
Profiling epigenetic mechanisms on a genome-wide
level using spatial-CUT&Tag
BY HANNAH HAN
ART BY SOPHIA ZHAO
Within each cell of the thirty
trillion that comprise your
body, bundles of threadlike
chromatin float in a nebulous shape
defined by the nucleus. This collection of
chromatin contains the human genome—
the catalog of genetic material that encodes
every cell, from the neurons in your brain
to the keratinocytes lining your skin. But
if each nucleus contains the same catalog
of genetic information, what differentiates
one cell from another? The answer lies
in the process of gene regulation—
which genes are activated and which are
repressed. This concept is fundamental to
the expanding field of epigenetics: the study
of how cellular mechanisms can change the
reading of genetic code without altering the
sequence of nucleotides itself.
Previous technologies have allowed
scientists to study these epigenetic changes
on a single-cell level by analyzing gene
or protein expression. However, these
methods required scientists to dissociate
the tissue section into individual cells
and to break those cells down further
for analysis. In doing so, researchers lost
spatial information that indicated where
the epigenetic regulations were occurring
within the tissue—details that were key to
understanding cellular function.
Researchers in the Fan Lab at Yale and
the Gonçalo Castelo-Branco Group at
the Karolinska Institute in Sweden have
developed a novel technique called spatial-
CUT&Tag. The method allows them to
map out epigenetic gene regulation in
the original tissue section using grids
composed of 20-micrometer pixels, an
area equivalent to a single neuron in the
brain. This technique represents a huge
leap forward in the field of spatial omics
and was recently published in Science.
“What has been missing in terms of
[past] technology is that you don’t really
see single-cell information in a kind of
genome-scale, unbiased way, [while it is]
still in the original tissue environment,” said
Rong Fan, a Yale professor of biomedical
engineering and the principal investigator at
the Fan Lab. “Over the past couple of years,
people realized how important that tissue
spatial information is in the development
of technology for spatial transcriptomics.
Now, we can see [gene regulation] pixel by
pixel, just like your TV.”
The Importance of Spatial-CUT&Tag in
Visualizing Histone Modifications
Fan and his colleagues focused on using
spatial-CUT&Tag to identify a specific
mechanism for epigenetic regulation, called
histone modification.
To understand the process of histone
modification, we first have to visualize
how DNA is packaged within the
nucleus. The average nucleus of a human
cell is only six micrometers in diameter,
22 Yale Scientific Magazine May 2022 www.yalescientific.org