Insulin regulatory sequence

Transcription of insulin is regulated by the binding of various transcription factors to the ~400 base pairs before the insulin transcription start site, called the "insulin regulatory sequence".^[1] This sequence is made up of several distinct regions with different biochemical properties, each of which serve as binding sites for distinct regulatory proteins. First, multiple A/T-rich sequences, called "A elements", each of which contains a "TAAT" reocognized by homeodomain proteins. These regions are primarily bound by PDX-1, but also Cdx2 and Isl-1.^[1] Second, two so-called "C elements" – C1 located 107–118 base pairs before the transcription start site; C2 311–317 base pairs before the start site. C1 is bound by RIPE3b1 via MafA. C2 (also called the "pancreatic islet cell enhancer sequence" or "PISCES") is bound by PAX6.^[1] Third, an "E element" (two in rodents) with sequence GCCATCTG is 91–100 base pairs before the transcription start site and binds the helix-loop-helix transcription factors NEUROD1.^[1] Lastly, several "cyclic AMP response elements" with sequence TGACGTCA that binds CREB.^[1]

In humans, a "Z-element" resides 243–292 base pairs before the start site and binds a complex called ZaI, as well as PDX-1 and MafA.^[1]

Regulatory sequences and their transcription factors for the insulin gene.^[2]

Regulatory sequence	binding transcription factors
ILPR	Par1
A5	Pdx1
negative regulatory element (NRE)[3]	glucocorticoid receptor, Oct1
Z (overlapping NRE and C2)	ISF
C2	Pax4, MafA(?)
E2	USF1/USF2
A3	Pdx1
CREB RE	CREB, CREM
A2	–
CAAT enhancer binding (CEB) (partly overlapping A2 and C1)	–
C1	–
E1	E2A, NeuroD1, HEB
A1	Pdx1
G1	–