Advancing Epigenetics Towards Systems Biology

EpiGeneSys bids farewell to Denise Barlow

It is with immense sadness that we learned that Denise Barlow, a great scientist and pioneer in the field of genomic imprinting, passed away on October 21st 2017 at the age of 67. Her contributions have inspired many scientists over the past decades and she was a deeply respected and highly appreciated member of the epigenetics community.

An obituary is available from the CEMM where Denise had worked for the last part of her career, up to her retirement in 2015.

Denise was a driving force in the modern era of epigenetics. She discovered one of the first imprinted loci – Igf2r – using a combination of classical mouse genetics together with (then) modern day physical mapping and molecular genetics approaches (Barlow et al, 1991) and showed how it was important for regulation of embryonic growth (Wang et al, 1991). She also discovered the region that controls its imprinting and showed that contrary to the dogma at the time, DNA methylation of this unique region correlated with Igf2r transcription rather than silencing (Stoger et al, 1993). She went on to reveal that this imprinting box regulated the imprinting of Igf2r through transcriptional interference and the expression of a very long (>100kb) non-coding RNA (that she gave the wonderful name “Air” for antisense to Igf2r) (Wutz et al, 1997, Lyle et al, 2001). She and her team single-handedly performed a long series of truly elegant experiments to address the control, requirements and functions of Air. They demonstrated that Air, like many lncRNAs we now know, functions both through the act of transcription across Igf2r (Sleutels et al, 2002) and through the role of the non-coding RNA at more distal loci (Latos et al, 2012), depending on the developmental context. She also was one of the first to propose that imprinting may have originally evolved as part of a defense system, against viruses, retroviruses and transposons (Barlow, 1993) – along the same vein as another great female scientist, Barbara McClintock. Denise Barlow’s dedication to understanding how imprinting at this complex locus is controlled and how it evolved are an example to us all in the field.

Her unique personality will also not be forgotten: she was demanding and rigorous as a scientist, unflinching in her questions; at the same time she was curious, humble and generous with her time when others sought her help. Her often seemingly “naïve” questions asked at seminars and meetings were usually the most profound and important ones – but she would say that this was just “The drive to see a biological problem with my own eyes” (from “Denise Barlow a career in Epigenetics”, RNA 2015). This singular approach to science – curious and unbiased – will never be forgotten. Denise was an active and passionate member of the Network of Excellence The Epigenome and remained connected to the EpiGeneSys community.

Denise was a splendid role model for many of us, and her loss is sorely felt. She was a fierce advocate of women in science. She also cared deeply about young scientists, helping to launch them in their successful independent careers. Her style and the scale and depth of her scientific achievements will live on however, thanks to her landmark discoveries - that still represent a reference in the study of epigenetics and non-coding RNAs - and thanks to the many people who she trained and influenced during her life.

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References

Barlow DP, Stoger R, Herrmann BG, Saito K, Schweifer N. The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus. Nature 1991; 349:84-7; PMID:1845916; http://dx.doi.org/10.1038/349084a0

Wang ZQ, Fung MR, Barlow DP, Wagner EF. Regulation of embryonic growth and lysosomal targeting by the imprinted Igf2/Mpr gene. Nature 1994; 372:464-7; PMID:7984240; http://dx.doi.org/10.1038/372464a0

Stoger R, Kubicka P, Liu CG, Kafri T, Razin A, Cedar H, Barlow DP. Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal. Cell 1993; 73:61-71; PMID:8462104; http://dx.doi.org/10.1016/0092-8674(93)90160-R

Wutz A, Smrzka OW, Schweifer N, Schellander K, Wagner EF, Barlow DP. Imprinted expression of the Igf2r gene depends on an intronic CpG island. Nature 1997; 389:745-9; PMID:9338788; http://dx.doi.org/10.1038/39631

Lyle R, Watanabe D, te Vruchte D, Lerchner W, Smrzka OW, Wutz A, Schageman J, Hahner L, Davies C, Barlow DP. The imprinted antisense RNA at the Igf2r locus overlaps but does not imprint Mas1. Nat Genet 2000; 25:19-21; PMID:10802648; http://dx.doi.org/10.1038/75546

Sleutels F, Zwart R, Barlow DP. The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature 2002; 415:810-3; PMID:11845212; http://dx.doi.org/10.1038/415810a

Latos PA, Pauler FM, Koerner MV, Senergin HB, Hudson QJ, Stocsits RR, Allhoff W, Stricker SH, Klement RM, Warczok KE, et al. Airn transcriptional overlap, but not Its LncRNA product, induces imprinted Igf2r silencing. Science 2012; 338:1469-1472; PMID:23239737; http://dx.doi.org/10.1126/science.1228110

Barlow DP. Methylation and imprinting: from host defense to gene regulation? Science 1993; 260:309-10; PMID:8469984; http://dx.doi.org/10.1126/science.8469984

Denise Barlow a career in Epigenetics (2015) RNA Biol. 12: 105–108. doi: 10.1080/15476286.2015.1018711