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Corrigendum

In the Abstract, the sentence "The A allele of rs8050136 associated with lower body mass than the C allele preferentially bound CUTL1 in human fibroblast DNA" should read "The A allele of rs8050136 preferentially bound CUTL1 in human fibroblast DNA". On page R1193 we state "Moreover, CUTL1 preferentially bound to DNA fragments carrying the ‘C’ allele of rs8050136". This should read "Moreover, CUTL1 preferentially bound to DNA fragments carrying the ‘A’ allele of rs8050136".

There have been discrepancies in the literature regarding the associations of obesity-related phenotypes with alleles of rs8050136. Scuteri et al. (2) associate the "C" allele with lower body mass index (BMI), whereas Tschritter et al. (3) associated the "C" allele of rs8050136 with higher BMI than the "A" allele. However, Tschritter et al. (3) inadvertently reversed the "A" and "C" alleles of rs8050136 in their paper (Erratum to: Diabetologia, Online: http://www.springerlink.com/content/k1150t348206t665/fulltext.pdf). The "A" (obesity-risk) allele of rs9939609 [Frayling et al. (1)] is in linkage disequilibrium (LD) with "A" allele of rs8050136 (McCarthy M, personal communication). Thus, it appears that the "A" allele of rs8050136 is the obesity-risk allele.

Our in vivo data indicate that Fto/Ftm are reduced in liver and adipose tissue of genetically obese mice and in hypothalamus and adipose tissue of fasted genetically obese and wild-type mice, consistent with one or both of these genes mediating suppressive effects on energy intake. As indicated in our manuscript, the transcription factor, CUTL1, binds preferentially to the "A" allele of rs8050136 in human fibroblasts, and RNAi-mediated knockdown of CUTL1 in these cells reduces the expression of FTO/FTM. To fit the physiological model that we proposed based on our in vivo and in vitro data, CUTL1 should preferentially bind to the rs8050136 allele associated with resistance to obesity. Since it does not, alternative models must be considered.

CUTL1 has the ability to increase or decrease transcription in specific cellular contexts. It is possible that, contrary to its stimulatory effects in skin fibroblasts, CUTL1 tonically suppresses FTO/FTM expression in neuronal or other (e.g., adipocyte) cell types. Enhanced binding/action at the "A" (obesity-risk allele) would lead to lower expression levels of FTO/FTM. This response is consistent with decreased expression levels of Fto/Ftm in genetically obese mice. It is also possible that CUTL1 is exerting its effects via another CUTL1 binding site in LD with rs8050136. There are multiple potential CUTL1 binding sites within the 47 kb region of LD (www.genomatix.de/online_help/help_matinspector/matinspector_help.html). Alternatively, FTO/FTM transcriptional control by CUTL1 is not functionally relevant in this context. Further experiments are clearly needed.

Figures 3, 5, and 8 are presented here correctly.

View larger version (70K): [in this window] [in a new window]   Fig. 3. Localization of Fto and Ftm transcripts in adult hypothalamus, pancreas, and 13.5 dpc embryo. Fto and Ftm expression by in situ hybridization in medial coronal hypothalamic (A) and sagittal pancreatic (B) sections from 4-wk-old C57BL/6J males. Positive alkaline phosphatase staining of Fto and Ftm transcript is seen as a dark perinuclear ring. Fto is expressed in the arcuate nucleus (ARC), the dorsal medial hypothalamus (DMH), and the ventral medial hypothalamus (VMH). Ftm expression is restricted to the ARC in the hypothalamus and is expressed at a lower level than Fto. C: Fto and Ftm in situ hybridization in medial sagittal sections of 13.5 dpc wild-type embryos. Positive alkaline phosphatase staining of Fto and Ftm is seen as a dark perinuclear ring. Fto expression is present in the whole embryo, particularly in the brain and spinal cord. In the brain, Fto expression is enriched in the ARC and mammillary area. Ftm is expressed mainly in the brain and appears restricted to the ARC and mammillary area. D: Fto and Ftm expression measured by real-time PCR in whole brains of 13.5 days post coitus (dpc) Lepob and +/+ mice. Transcript levels were normalized to Gapdh.

View larger version (17K): [in this window] [in a new window]   Fig. 5. Fig. 5. Comparison of Fto and Ftm expression in various tissues and obesity models. Fto and Ftm expression quantified by qPCR in mesenteric fat (A), subcutaneous fat (B), liver (C), and hypothalamus (D) of Leprdb, Cpefat, tub, diet-induced obese C57BL/6J (DIO), DIO C57BL/6J control (DIO C), and chow-fed +/+ C57BL/6J mice. Transcript levels were normalized with Gapdh; n = 5 each group.

View larger version (20K): [in this window] [in a new window]   Fig. 8. CUTL1 regulates the transcription of FTO and FTM. A: rs17817449 and rs8050136 are located within CUTL1 recognition sequences as identified by MatInspector (Genomatix; http://www.genomatix.de). Complementary mouse sequence is aligned to the human sequence. Bases that fit the consensus are highlighted. B: LightCycler chromatogram showing the crossing point of PCR reactions containing DNA fragments isolated by ChIP with CUTL1, HES1, and mouse IgG antibodies. C: pyrosequencing using DNA extracts isolated by ChIP with the Cutl1 antibody. Genomic DNA isolated from fibroblasts heterozygous for rs8050136 (A/C) was used as a control. D: expression analysis of CUTL1, FTO, and FTM in human fibroblasts heterozygous for rs8050136 (A/C), where CUTL1 has been knocked down with siRNA.

REFERENCES

1. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316: 889–894, 2007.[Abstract/Free Full Text]
2. Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, Najjar S, Nagaraja R, Orru M, Usala G, Dei M, Lai S, Maschio A, Busonero F, Mulas A, Ehret GB, Fink AA, Weder AB, Cooper RS, Galan P, Chakravarti A, Schlessinger D, Cao A, Lakatta E, Abecasis GR. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 3: e115, 2007.[CrossRef][Medline]
3. Tschritter O, Preissl H, Yokoyama Y, Machicao F, Haring HU, Fritsche A. Variation in the FTO gene locus is associated with cerebrocortical insulin resistance in humans. Diabetologia 50: 2602–2603, 2007.[CrossRef][Web of Science][Medline]

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