April 2022, ScientificAmerican.com 15ing to be transcribed. That idea began to
unravel in 1994, when Low discovered that
a chemical tag called a methyl group could
block transcription in bacteria—something
scientists had thought was exclusive to
eukaryotic cells.
More similarities have emerged over
the years. For example, eukaryotic cells
attach chemical tags and proteins called
histones to hide away parts of the ge -
nome. Last year Freddolino’s laboratory
showed that bacteria use an analogous
strategy: the researchers identified 200
regions in the Escherichia coli genome that
are silenced using chemical tags and struc-
tures called nucleoid-associated pro-
teins (NAPs).
For a recent study in the EMBO Journal,
Freddolino demonstrated that NAPs worked
similarly to silence specific sections of the
bacterial genome in distantly related spe-
cies E. coli and Bacillus subtilis. The NAP
acts as a scaffold around which a portion
of DNA gets wrapped, making it physically
impossible for the cell’s protein-making
machinery to access genes in that portion.
This effect is critically important for bacte-
ria: it allows them to seal off snippets of
outside DNA and viruses that have
wedged their way into the bacterial
genome, and it lets them wall off rarely
used genes when they are not needed.
NAPs do not work alone, however. To
determine what triggers them to switch
off sections of DNA, Freddolino and Jakob
turned their attention to polyphosphate.
This molecule was used for energy storage
by Earth’s early life and has evolved a vari-
ety of functions in cells. In 2020 Jakob
found that mutant E. coli unable to synthe-
size polyphosphate showed more activity
in genes absorbed from outside the cell—
and that this activity plays a key role in cell
death from DNA damage.
Recently, in Science Advances, Jakob
and Freddolino showed that negatively
charged polyphosphate binds to positively
charged NAPs using a process called liq-
uid-liquid phase separation, in which ultra-
dense protein groups condense into tiny
droplets. As more and more polyphos-
phate attaches to the NAPs, the normally
scattershot structure of polyphosphate,
NAPs and DNA becomes organized. Just
as oil droplets can form in even a well-
mixed vinaigrette, droplets of protein,
DNA and polyphosphate can congeal inbacterial cells—and this blocks parts of the
genome from transcription. The process
does not need additional helper proteins,
and it can be reversed when polyphos-
phate levels drop.
These studies are a major step in
under standing bacterial epigenetics, says
University of Leiden biochemist Remus
Dame, who was not involved in either
study. “There’s good reason to believe that
the global structure in which these genes
are embedded dictates how active they
are,” he says. “This is really something
very new—and very hot—that means
we have to look differently at our system
of interest.”
Freddolino says that when his biotech-
nology-focused colleagues first learned
of these results, they began using this
knowledge to insert engineered genes
into spots along the bacterial genome
that optimize protein production. The pro-
cess, he says, has since gone from “cross
your fingers and hope for the best” to
a sound strategy that works almost
every time.
At the Massachusetts Institute of
Technology, biochemist Peter Dedon is
investigating how scientists can make
new antibiotics using these mechanisms.
Work from his lab (and others around the
world) shows that bacteria switch genes
on and off to help infect hosts—and to
resist antibiotics. Dedon envisions a small
molecule that could interfere with this
process and keep a bacterium’s infection-
boosting characteristics or antibiotic
resistance genes switched off; another
option would be to disrupt polyphos-
phate’s ability to bind to NAPs. This would
not kill bacteria outright, but it would ren-
der them less able to cause disease and
more susceptible to immune system
attacks. “There’s great potential there,”
Dedon says. “There’s a whole new world
of antibiotic targets.”
Bacterial epigenetics is an excellent
focus for antibiotic development, Jakob
says, because its mechanisms are shared
across many bacteria species—but use
fundamentally different proteins than
eukaryotic cells do. This means research-
ers can specifically target bacterial pro-
teins and avoid interfering with the body’s
own epigenetic processes, Jakob says: “It’s
a way to prevent disease without needing
to kill the cell.” — Carrie Arnolding to be transcribed. That idea began to
unravel in 1994, when Low discovered that
a chemical tag called a methyl group could
block transcription in bacteria—something
scientists had thought was exclusive to
eukaryotic cells.
More similarities have emerged over
the years. For example, eukaryotic cells
attach chemical tags and proteins called
histones to hide away parts of the ge -
nome. Last year Freddolino’s laboratory
showed that bacteria use an analogous
strategy: the researchers identifi ed 200
regions in the Escherichia coli genome that
are silenced using chemical tags and struc-
tures called nucleoid-associated pro-
teins (NAPs).
For a recent study in the EMBO Journal,
Freddolino demonstrated that NAPs worked
similarly to silence specifi c sections of the
bacterial genome in distantly related spe-
cies E. coli and Bacillus subtilis. The NAP
acts as a scaff old around which a portion
of DNA gets wrapped, making it physically
impossible for the cell’s protein-making
machinery to access genes in that portion.
This eff ect is critically important for bacte-
ria: it allows them to seal off snippets of
outside DNA and viruses that have
wedged their way into the bacterial
genome, and it lets them wall off rarely
used genes when they are not needed.
NAPs do not work alone, however. To
determine what triggers them to switch
off sections of DNA, Freddolino and Jakob
turned their attention to polyphosphate.
This molecule was used for energy storage
by Earth’s early life and has evolved a vari-
ety of functions in cells. In 2020 Jakob
found that mutant E. coli unable to synthe-
size polyphosphate showed more activity
in genes absorbed from outside the cell—
and that this activity plays a key role in cell
death from DNA damage.
Recently, in Science Advances, Jakob
and Freddolino showed that negatively
charged polyphosphate binds to positively
charged NAPs using a process called liq-
uid-liquid phase separation, in which ultra-
dense protein groups condense into tiny
droplets. As more and more polyphos-
phate attaches to the NAPs, the normally
scattershot structure of polyphosphate,
NAPs and DNA becomes organized. Just
as oil droplets can form in even a well-
mixed vinaigrette, droplets of protein,
DNA and polyphosphate can congeal inbacterial cells—and this blocks parts of the
genome from transcription. The process
does not need additional helper proteins,
and it can be reversed when polyphos-
phate levels drop.
These studies are a major step in
under standing bacterial epigenetics, says
University of Leiden biochemist Remus
Dame, who was not involved in either
study. “There’s good reason to believe that
the global structure in which these genes
are embedded dictates how active they
are,” he says. “This is really something
very new—and very hot—that means
we have to look diff erently at our system
of interest.”
Freddolino says that when his biotech-
nology-focused colleagues fi rst learned
of these results, they began using this
knowledge to insert engineered genes
into spots along the bacterial genome
that optimize protein production. The pro-
cess, he says, has since gone from “cross
your fi ngers and hope for the best” to
a sound strategy that works almost
every time.
At the Massachusetts Institute of
Technology, biochemist Peter Dedon is
investigating how scientists can make
new antibiotics using these mechanisms.
Work from his lab (and others around the
world) shows that bacteria switch genes
on and off to help infect hosts—and to
resist antibiotics. Dedon envisions a small
molecule that could interfere with this
process and keep a bacterium’s infection-
boosting characteristics or antibiotic
resistance genes switched off ; another
option would be to disrupt polyphos-
phate’s ability to bind to NAPs. This would
not kill bacteria outright, but it would ren-
der them less able to cause disease and
more susceptible to immune system
attacks. “There’s great potential there,”
Dedon says. “There’s a whole new world
of antibiotic targets.”
Bacterial epigenetics is an excellent
focus for antibiotic development, Jakob
says, because its mechanisms are shared
across many bacteria species—but use
fundamentally diff erent proteins than
eukaryotic cells do. This means research-
ers can specifi cally target bacterial pro-
teins and avoid interfering with the body’s
own epigenetic processes, Jakob says: “It’s
a way to prevent disease without needing
to kill the cell.” — Carrie Arnoldsad0422Adva3p.indd 15sad0422Adva3p.indd 15 2/16/22 6:59 PM2/16/22 6:59 PM
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