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A master regulator of regeneration

Study of panther worm reveals a pioneer transcription factor that regulates regeneration

By Michael Alonge1 and scription, it was shown that they could the epigenetic landscape needed for nor-
Michael C. Schatz1,2,3 independently bind and open compacted mal gene regulation (7).
chromatin at this locus in vitro (5). Several Owing to the lack of a reference genome

ofstenia miamia, commonly called additional pioneer factors have since been for H. miamia, Gehrke et al. assembled
the three-banded panther worm, is identified by studying local chromatin ac- and annotated a reference genome to en-
a small flatworm that can be found cessibility and epigenetic dynamics, such able genome-wide research of whole-body
along the shores of the Caribbean as histone modifications or DNA methyla- regeneration. Importantly, their approach
and other warm waters. It is known tion, across key stages of cell development. of combining high-throughput short-read
for its impressive regenerative capa- As more pioneer factors are discovered in DNA sequencing with long-range chroma-
bilities, including the ability to regenerate diverse systems, their characterization will tin conformation mapping data using the
any body part within a few days of ampu- be crucial for understanding cell fate and “Chicago” protocol (8) led to a chromo-
tation. Previous reports identified some of reprogramming, as they have the capa- some-scale assembly with more than 90%

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the molecular signals used to coordinate bility to initiate transcription of develop- of the genes assembled along with their
regeneration (1), although the specific mentally silenced genes. For example, the flanking regulatory sequences. This level
genes and gene networks that regulate this expression of certain pioneer factors has of assembly quality was crucial to iden-
response were unknown. On page 1191 of been demonstrated to transdifferentiate fi- tifying transcription factor binding sites
this issue, Gehrke et al. (2) developed an broblasts into functional neurons (6), and and studying chromatin architecture. This
impressive collection of genomic resources mutations of FoxA pioneer factors play an work also highlights the recent advances
for the species, including extensive DNA, important role in many cancers by altering in modern genome assembly technology,
RNA, and chromatin accessibility data to which allow researchers to quickly produce
promote H. miamia as a new model sys- relatively inexpensive yet highly accurate
tem for studying regeneration. Using these Genomics of regeneration reference assemblies of uncharacterized
data, they identify early growth response eukaryotic species (9).
(Egr), which encodes a candidate pioneer
in Hofstenia miamia The availability of a high-quality ref-
Chromatin accessibility and gene expression data
transcription factor responsible for regu- erence genome opened the door to ex-
collected post-amputation in H. miamia suggest
lating the molecular regenerating response that the early growth response (Egr) transcription
periments to uncover the gene regulatory
to wounding. factor (TF) is a pioneer factor that can bind to networks involved in whole-body regen-
In eukaryotic cells, meters of genomic closed chromatin, rearrange nucleosomes to allow eration. Gehrke et al. collected chromatin
DNA are tightly packed into protein-DNA transcription, and thereby activate the expression accessibility data (ATAC-seq, or assay for
structures called chromatin. The extent of of genes needed for regeneration. transposase-accessible chromatin using
DNA compaction or accessibility in chro- sequencing) (10) and gene expression data
matin facilitates cell type–specific gene (RNA-seq) from regenerating cells at mul-
H. miamia
regulation by physically blocking or per- tiple time points following amputation.
mitting regulatory DNA binding proteins, The results showed that Egr binding was
called transcription factors. Pioneer fac- strongly associated with chromatin accessi-
tors are a class of transcription factors bility during regeneration and that Egr was
that are unique in their ability to indepen- also the most significantly up-regulated
dently and initially bind their DNA target gene early in wounded cells. Gehrke et al.
sequences in “silent” compacted chroma- Bind Pioneer factor performed focused experiments to demon-
tin. Through actively establishing DNA ac- Nucleosome
strate that Egr is a master regulator of a
cessibility, recruiting other transcription gene regulatory network for whole-body
factors, and/or triggering local epigenetic regeneration composed of at least 61 genes.
changes, pioneer factor binding can prime Further analysis showed that Egr has pio-
genes for positive or negative regulation Rearrange Recruitment of additional TFs neer factor–like properties, especially the
(3). The first pioneer factors, forkhead box TF rapid and complete transition from closed
Egr TF
protein A (FoxA) and GATA binding factor to open chromatin states near Egr binding
4 (Gata4), were identified in studies of the sites during regeneration (11) (see the fig-

serum albumin gene Alb1 during mouse ure). Additionally, using ATAC-seq follow-
hepatic differentiation (4). Although it was Activate Wound response gene expression ing amputation in the planarian Schmidtea
previously known that these transcription TF mediterranea, a classic model system for
factors were recruited early for Alb1 tran- Egr TF regeneration (12), they showed a simi-
lar chromatin response near Egr binding
sites. This finding suggests that the regen-
Department of Computer Science, Johns Hopkins University, eration response to amputation and the
Baltimore, MD, USA. 2Department of Biology, Johns Hopkins
University, Baltimore, MD, USA. 3Cold Spring Harbor Laboratory, Regeneration pioneer factor activity for Egr originated
Cold Spring Harbor, NY, USA. Email: in the common ancestor of H. miamia and

1152 15 MARCH 2019 • VOL 363 ISSUE 6432 SCIENCE

Published by AAAS
S. mediterranea some ~550 million years ANCIENT DNA
ago and potentially will be present in other
bilaterians such as humans.
The study by Gehrke et al. presents sev-
eral avenues for future research. With H.
Toward a clearer view into
miamia, additional genomic studies are
needed to fully characterize the role of human prehistory
Egr, such as examining chromatin bind-
ing across different cell types and phases An ancient DNA study highlights ancient population
of regeneration. Additional biochemical patterns on the Iberian Peninsula
studies are also needed to determine the
specific mechanisms used by Egr to open
compacted chromatin and if this can be By Marc Vander Linden that each sample provides a wealth of in-
done completely independently of any formation about entire past lineages, recent

other factors. Beyond H. miamia, this early a decade has passed since the research on the European Bell Beaker phe-
experimental design can be followed in first ancient genome of a human was nomenon demonstrates that more than 200
other highly regenerative species, such as sequenced. Since then, rapidly increas- samples were required to start encapsulating,
Macrostomum lignano (13), that have or- ing numbers of such sequences have in genomic terms, the complexity of the past
thologs of Egr to discover additional pio- revealed the complex role of admixture evident in archaeological data (2).
neer factors. Notably, orthologs of Egr are in human societies and evolution. Ad- Yet, it is naïve to assume that more data

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known to play an important role in human mixture is especially evident in studies sam- are always necessary. Ancient DNA research
biology, including regulating a variety of pling a given area over the long term, such as involves the destructive sampling of a finite
growth factors and tumor suppressors (14), those reported on page 1230 of this issue by resource, and it is therefore imperative to
although there are no reports of it as a pio- Olalde et al. (1) for the Iberian Peninsula. The evaluate the cost to irreplaceable resources
neer factor. This work is also a testament authors report changes in the direction of and the benefits of knowledge gained. Given
to how modern genome sequencing and gene flow between this region and neighbor- the self-acknowledged backlog of unpub-
functional genomics techniques present ing ones through time and how these changes lished samples already generated by certain
relate to cultural history. Given that this and laboratories [(6), p. 16], cynics might be
“This work also highlights the other studies rely upon increasing datasets, tempted to call for a temporary embargo on
it is worth considering the balance between destructive analyses until we have learned
recent advances in moderm knowledge gained and the practicalities and how or whether the samples in the queue have
ethics of destructive sampling. changed the state of knowledge, whether new
genome assembly technology, Olalde et al. retraced events that shaped ge- questions have arisen, and what further data
which allow researchers to nomic variation in the Iberian Peninsula, in- might be helpful to advance the field.
cluding a more complex population structure As with any destructive technique and
quickly produce...reference of the last foragers than previously thought given the cost of ancient DNA sequencing,
assemblies...” and a possible total replacement of the lo- simultaneous sampling for additional infor-
cal male population by people with Steppe mation should be undertaken systematically.
an opportunity for studying the molecular ancestry during the Bronze Age, a pattern For example, many samples are radiocarbon
biology of non–model species. Researchers comparable to that seen in Bronze Age Brit- dated, but others are not, including those re-
should be encouraged to explore broadly ain (2). They also document gene flow from ported by Olalde et al. Aside from mitigating
across species and then attack the molecu- North Africa and the eastern Mediterranean sample destruction, there are analytical ad-
lar mechanisms of their phenotypes using during Classical and Medieval periods, thus vantages to iterative sampling. By combining
all the experimental and computational echoing known historical processes. Other ancient DNA sequencing with stable isotope
tools available. j identified events are perhaps less expected, and material culture studies, Knipper et al.
such as the presence of a Northern African showed that most Early Bronze Age women
genomic component during the Chalcolithic in the Lech valley (southern Germany) were
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Genet. 19, 329 (2018). relatedness cannot be conflated with social nized around biological kinship, with genetic
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Greenleaf, Nat. Methods 10, 1213 (2013).
or cultural identities (5). Many archaeolo- differences echoed in diet, mobility patterns,
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samples that are unevenly distributed across It is worth remembering that different se-
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Mercola, Cancer Gene Ther. 13, 115 (2006). gle-nucleotide polymorphism, whole-genome
Department of Archaeology, University of Cambridge, capture, and shotgun sequencing—differ in
10.1126/science.aaw6258 Cambridge, UK. Email: costs, scientific outputs, and how much en-

SCIENCE 15 MARCH 2019 • VOL 363 ISSUE 6432 1153

Published by AAAS
A master regulator of regeneration
Michael Alonge and Michael C. Schatz

Science 363 (6432), 1152-1153.

DOI: 10.1126/science.aaw6258

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